Startseite SLC25 family with energy metabolism and immunity in malignant tumors
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SLC25 family with energy metabolism and immunity in malignant tumors

  • Guiqian Zhang , Ning Wang , Shixun Ma , Zhenhong Wei , Pengxian Tao EMAIL logo und Hui Cai ORCID logo EMAIL logo
Veröffentlicht/Copyright: 6. Dezember 2023
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Oncologie
Aus der Zeitschrift Oncologie Band 26 Heft 1

Abstract

Solute Carrier Family 25 (SLC25) is the largest family of mitochondrial membrane proteins in the human body, consisting of 53 members. Mitochondrial phosphate carriers (MPiC), cellular iron metabolism, voltage-dependent anion channels (VDAC), and oxidative phosphorylation in the SLC25 family play dominant roles in material transport, energy metabolism, etc. SLC25 family-related proteins are involved in the regulation of the progression of a variety of cancers, including colon, gastric, and lung cancers. In addition, the SLC25 family has been implicated in endoplasmic reticulum stress (ERS) and immunity. Since SLC25 family proteins are involved in cancer progression and are associated with endoplasmic reticulum stress and immunity, exploring inhibitors of SLC25 family-related proteins is essential. However, the exact mechanism of SLC25 family-related proteins involved in cancer, as well as potential targets and SLC25 inhibitors have not been reported in the literature. This article focuses on summarizing the relevance of the SLC25 family to cancer, ERS, and immunity. This review also provides a comprehensive overview of SLC25 family-related inhibitors.

Keywords: SLC25 family; energy metabolism; endoplasmic reticulum stress; inhibitors; immunity; cancer

Introduction

The solute carrier family 25 (SLC25), consisting of 53 members and characterized by six transmembrane helices, represents the largest group of mitochondrial inner membrane proteins in humans [1]. The SLC25 family members, also known as MCFs or MCs, consist of three identical homologous structures that are approximately 100 amino acids long. MCs can be categorized into six classes based on the specificity of their substrates, including amino acids, nucleotides and dinucleotides, carboxylic and keto acid carriers, and other substrates. Each class can be further subdivided into citrate (CIC), phosphate (PIC), ADP and ATP (AAC), dicarboxylate (DIC), aspartate, glutamate (AGC), and sulfate (UCPs) subgroups [2], [3], [4]. These proteins play a crucial role in various physiological processes, including oxidative phosphorylation, catabolism, protein interconversion, synthesis of blood cell components, and thermogenesis [2].

According to the literature, we found that SLC25 family members have important effects on cancer, endoplasmic reticulum stress and immunity [5], [6], [7]. Intriguingly, since the development of cancer is inextricably linked to energy metabolism [8]. As a significant determinant of energy metabolism, alterations in the SLC25 family can have profound implications. Specifically, DNA mutations or aberrant expression of the SLC25 gene have been implicated in the pathogenesis of carcinogenesis through metabolic dysregulation [5]. For instance, the inhibition of mitochondrial function in colon cancer is facilitated by SLC25A14 through a feedback mechanism [9]. Similarly, the disruption of hepatocellular carcinoma (HCC) cell growth is caused by the downregulation of SLC25A11 [10]. The involvement of the SLC25 family in endoplasmic reticulum stress (ERS) has been reported. Additionally, the activation of peroxisome proliferator-activated receptors (PPARs β/δ) restores bacterial endotoxin lipopolysaccharide (LPS)-induced endothelial dysfunction by upregulating SLC25A8, which subsequently alleviates ERS [11]. Furthermore, a study indicates a negative correlation between CD8 and SLC25A5 in colon cancer patients [9].

However, there is a lack of comprehensive research on the impact of the SLC25 family on various cancers, endoplasmic reticulum stress (ERS), and immunity. Therefore, this review aimed to specifically examine the effects of the SLC25 family on cancer, ERS, and immunity.

SLC25 family

The SLC25 family includes mitochondrial ADP/ATP carriers, mitochondrial ATP-MG/Pi carriers, inorganic ion transports, and amino acid transports. Details of the SLC25 family protein members are shown in Table 1.

Table 1:

SLC25 family-related proteins.

Carriers Symbol (SLC25) Alias/alternate symbol Target/description/reference
Mitochondrial ADP/ATP carriers SLC25A4 AAC1 The four isoforms of this vector are expressed in a tissue-dependent manner [12].
SLC25A5 AAC2
SLC25A6 AAC3
SLC25A31 AAC4
Mitochondrial ATP-MG/Pi carriers SLC25A24 APC1 It consists of an N-terminal calcium regulatory domain with four EF hands, a biphasic structural domain and a C-terminal carrier domain that transports substrates [13], [14], [15], [16]. However, SLC25A41 lacks the regulatory structural domain [17].
SLC25A23 APC2
SLC25A25 APC3
SLC25A41 APC4
Mitochondrial phosphate carrier SLC25A3 PHC ATP synthesis [18].
Uncoupling protein SLC25A7 UCP1 Mainly found in the brown adipose tissue of newborn mammals, producing heat for the body [19].
SLC25A8 UCP2
SLC25A9 UCP3
SLC25A27 UCP4
SLC25A14 UCP5
SLC25A30 UCP6
Aspartate/glutamate carriers SLC25A12 AGC1 Acts on gluconeogenesis, bone marrow synthesis, malic acid-aspartic acid shuttle and urea cycle [20].
SLC25A13 AGC2
Thiamine pyrophosphate transporter SLC25A19 TPC The main function is to transport thiamine pyrophosphate [21].
Carnitine/acylcarnitine carrier SLC25A20 CAC Import of acylcarnitine into mitochondria with simultaneous export of carnitine [22].
Mitochondrial ketoglutarate carrier SLC25A11 OGC Involved in the exchange of malic acid and 2-oxoglutamic acid [23].
Tricarboxylic acid or citrate carrier SLC25A1 CIC Export of citrate from mitochondria to the cell membrane [24].
Basic amino acid carrier SLC25A29 BAC Involved in the transport of amino acids such as arginine [25].
Dicarboxylate carrier SLC25A10 DIC Maintenance of inorganic phosphate in the mitochondrial matrix [2].
Glutamate carrier SLC25A18 GC2 Involved in the transport of glutamate [26].
SLC25A22 GC1
Glycine carrier SLC25A38 GLYC Transport of glycine into mitochondria [27].
Mitoferrin SLC25A28 MFRN2 Transport of iron ions into mitochondria [28].
SLC25A37 MFRN1
Oxoadipate carrier SLC25A21 ODC Input 2-oxoadipic acid and output 2-oxoglutaric acid [29].
Ornithine carrier SLC25A2 ORC2 Catalyzing the exchange of ornithine and citrulline [17].
SLC25A15 ORC1
S-adenosylmethionine carrier SLC25A26 SAMC Transport of S-adenosylmethionine into mitochondria with simultaneous output of the product S-adenosylhomocysteine [17].
Pyrimidine nucleotide carriers SLC25A33 PNC1 For the synthesis and breakdown of mitochondrial DNA and RNA [30, 31].
SLC25A36 PNC2
Branched-chain amino acids SLC25A44 KIAA0446 Provides metabolic energy and heat production [32].
Mitochondrial folate transporter SLC25A32 MFTC Transport of folic acid and flavin [18, 33].
Mitochondrial CoA transporter SLC25A42 MECREN Transport of coenzyme A [12]
Uncharacterized carriers SLC25A43 Regulator of cell cycle progression and proliferation [34].

SLC25’s mode of energy metabolism

Mitochondria are important organelles that maintain cell homeostasis and play an important role in cell metabolism. It has been reported that the mitochondrial temperature of cancer cells may be relatively higher than that of normal cells, suggesting hyper respiration of mitochondria in cancer cells, and further confirmed that mitochondrial temperature in tumors is relatively higher than that in paracancerous tissues through surgically resected human tumors [8]. Meanwhile, mitochondrial temperature-responsive drugs can reverse cancer drug resistance [35], [36], [37]. Mitochondrial temperature response provides important evidence for cancer metabolism. Abnormal expression of SLC25 family genes may lead to carcinogenesis when there is an imbalance in energy metabolism. For example, mutations or abnormal expression of SLC25A11 can lead to tumorigenesis through metabolic abnormalities [5]. SLC25A11 Gene mutations may be associated with metastatic paraganglioma [38]. We summarized the tumors associated with this protein family, as shown in Table 2 below.

Table 2:

SLC25 family-related tumors.

Cancer Author and year of report SLC25 family member Mechanism
Colon cancer 2022. Luby [39] SLC25A8 Tumor differentiation.
2010. Kuai [40] SLC25A14 Feedback mechanism.
2020. Liang [41] SLC25A18 Inhibiting the Wnt/β-catenin.
2022. Chen [9] SLC25A5 and SLC25A24 EGFR and ERK-MAPk pathways.
Gastric cancer 2015. Russo [42] SLC25A4 Down-regulation in gastric cancer tissues.
Lung cancer 2016. Jang [43], [44], [45] SLC25A5 PI3K/AKT pathway.
2018. Fernandez [46] SLC25A1 Tumor cell metabolism.
2015. Zhou [47, 48] SLC25A10 Reduced overall survival.
Breast cancer 2018. Hlouschek [47, 48] SLC25A10 Reduced overall survival.
2012. Tina [49] SLC25A43 Absent in HER 2+ breast cancer.
2012. Tina [49] SLC25A33 Cell proliferation.
Liver cancer 2016. Jang [43], [44], [45] SLC25A5 PI3K/AKT pathway.
2018. Baulies [50] SLC25A10 and SLC25A11 Adaptive mechanism.
2019. Infantino [10, 51] SLC25A12 Promote cell growth and migration.
Chronic myeloid leukemia 2017. Nawin [52] SLC25A3 High expression.
Acute monocytic leukemia 2023. Chaudhary [53] SLC25A4 Associated antigen.
Renal cancer 2012. Kim [54] SLC25A4 Highly correlated with BCL2L13.
Prostate cancer 2015. Russo [42] SLC25A4 Cancer-related fatigue.
Bladder cancer 2021. Wang [55] SLC25A21 Oxidative stress.
Glioblastoma 2018. Finsterer [56, 57] SLC25A4 The loss of mitochondrial DNA or multiple mitochondrial.
Neuroblastoma 2010. Kwok [58] SLC25A14 Overexpression reduces ROS accumulation.

PiC

PiC, which belongs to the SLC25 family, consists of two isoforms: PiC A and PiC B. PiC is the primary pathway for the entry of inorganic phosphate into the mitochondrial matrix and plays a key role in oxidative phosphorylation [59]. PiC is involved in ATP synthesis, so that all metabolites required for ATP production are located within a direct microstructural domain [60]. PiC is encoded by the nuclear gene SLC25A3, the deletion of which has been shown to cause dysregulation of ATP synthesis, as observed in patients with mutations in skeletal muscle-specific genetic subtypes [61, 62]. SLC25A3 has been reported to play a role in glucose-stimulated insulin secretion from pancreatic islet β-cells, in which the increase in ATP is imbalanced with the decrease in ADP [63]. SLC25A3 transports phosphate and copper, and its deletion reduces mitochondrial copper levels. In addition, SLC25A3 is an essential mitochondrial copper transporter for cytochrome C oxidase biogenesis [64]. SLC25A3 is located on chromosome 12 (at 12q23), acts as a carrier for the transport of phosphate into the mitochondrial matrix, and is highly expressed in chronic myeloid leukemia [52]. In summary, patients with abnormal SLC25A3 expression are often characterized by certain multisystem diseases, including reduced myotonia, hypertrophic cardiomyopathy, and lactic acidosis [61, 65].

Cellular iron

Iron, an integral part of the body, plays an important role in electron transport, oxygen transport, deoxyribonucleotide synthesis, hemoglobin metabolism, and iron–sulfur cluster protein metabolism [66]. Mitochondria are closely associated with the regulation of cellular iron, and iron is directly or indirectly involved in reactive oxygen species (ROS) production through the Fenton reaction and the Haber–Weiss reaction [59]. SLC25A28 and SLC25A37 are two important transporters among many regulatory factors [67]. PTEN induced putative kinase 1(PINK1) and Recombinant Parkinson Disease Protein 2 (PARK2) control pancreatic tumorigenesis through mitochondrial iron-dependent immunometabolism [68]. The PINK1–PARK2 pathway-mediated autophagic degradation of SLC25A37 and SLC25A28 inhibits pancreatic tumor growth by attenuating mitochondrial iron accumulation, inflammasome activation, high mobility group protein B1(HMGB1) release, and subsequent immune checkpoint expression [68, 69]. The zebrafish mutant frascati is known to display severe hypochromic anemia and erythrocyte maturation arrest because of faulty mitochondrial iron uptake [70]. It has been shown that mature erythrocytes produced from mitochondrial ferritin (MFRN)-invalid mouse embryonic stem cells (also known as SLC25A37) display maturation arrest and severely impaired 55Fe entry into erythrocytes [71]. In conclusion, most diseases related to cellular iron metabolism in mitochondria are associated with SLC25A28 and SLC25A37.

VDACs

Adenine nucleotide transporter (ANT) is a protein found abundantly on the inner mitochondrial membrane (IMM) and is mainly involved in ADP/ATP exchange [2]. Human ANT has four isoforms (ANT1-4) encoded by different genes: SLC25A4, SLC35A5, SLC25A6, and SLC25A31. Under physiological conditions, VDACs and ANT are functionally coupled to enable the efficient transfer of metabolites, and VDAC1 and ANT have a direct interaction at the structural level [72]. VDACs are present in the outer mitochondrial membrane (OMM) of all eukaryotes and have various structural states and selectivity. They perform the function of facilitating and regulating the movement of metabolites across the cytoplasmic and mitochondrial membrane space, thereby functioning as a membrane channel. VDACs regulate various cellular processes, including apoptosis, metabolism, and calcium homeostasis, and affect many diseases, such as cancer, neurodegenerative diseases, and cardiovascular diseases. VDACs in mitochondria have been reported to play a dual role and their action is related to PiC [73]. In mammals, VDACs include VDAC1, VDAC2, and VDAC3. VDAC1 is mainly found in cardiac mitochondria and OMM and regulates different damage levels together with oxidative stress [74] (such as myocardial ischemia–reperfusion). VDAC1 is a major target in the war against cancer [75]. VDAC1 expression was significantly higher in most cancer cell lines than in normal cell lines. VDAC1 and hexokinase interacted with each other to facilitate energy production while preventing cell death, leading to abnormal proliferation [76]. Therefore, severing the link between the two is the focus of cancer therapies targeting VDAC1 [77]. Meanwhile, Antp-LP4 was among the most optimal VDAC1-based peptides tested to induce cell death [78]. VDAC2 is voltage-dependent and selective for anions [67], and it affects tumor progression through apoptosis. VDAC2 is involved in anti-apoptosis via the specific interaction and inhibition of Bakau virus (Bak) [79]. Upregulated VDAC2 has a role in melanoma cells, thyroid epithelial tumor cells, and mesothelioma, resulting in reduced Bak expression [80, 81]. Of note, VDAC2-silenced cells were more susceptible to the anticancer drug sorafenib [77]. Therefore, VDAC2 may be a highly prospective anti-cancer target. VDAC3 is a promising marker of the oxidative state of the mitochondria in cancer [82]. In addition, VDAC3, highly expressed in testes and sperm, interacts with various other proteins to build a network that controls cancer [83]. Finally, applied erastin, which acts on VDAC3, to cells, and the results showed changes in the porosity of OMM [84]. Thus, VDAC3 is an interesting candidate for anticancer therapy.

Mitochondrial oxidative phosphorylation (OXPHOS)

OXPHOS is one of the mitochondrial metabolic functions that consist of the respiratory chain and ATP synthesis. The respiratory chain oxidizes nicotinamide adenine dinucleotide (NADH) and flavine adenine dinucleotide (FADH2), transfers electrons to oxygen, and uses the energy released by electron transfer to pump hydrogen ions into the intermembrane space, thereby establishing a proton gradient on both sides of IMM [85]. The proton gradient is consumed during ATP synthesis. Most mitochondrial diseases are caused by defects in OXPHOS, which reduce mitochondrial membrane potential, inhibit the transitional transport of mitochondrial proteins and metabolites, and disrupt mitochondrial production and cytoplasmic protein homeostasis [86, 87]. During OXPHOS, a small fraction of electrons leak to O2 to form superoxide, which subsequently forms ROS, reactive nitrogen species (RNS), and nitric oxide synthase (NOS) [88, 89]. The overproduction of ROS and RNS has been linked to several diseases affecting the immune system, cardiovascular system, and neurons [74].

In healthy settings, mitochondrial transporters in IMM and OMM tightly regulate OXPHOS homeostasis. Thus, to maintain cellular homeostasis, the relative balance between ATP synthesis and ROS function must be controlled. In this regard, mitochondrial uncoupling proteins (UCPs) are essential for ensuring stability. UCP1 regulates proton flow through ATP synthesis, and the ubiquitous UCP2 is associated with metabolic diseases, cardiovascular diseases, and cancer [90]. UCP2 (SLC25A8) was discovered as a new therapeutic target for human epidermal growth factor receptor 2(HER2)-positive breast cancer [91]. SLC25A8 has been reported to be upregulated in colon cancer and associated with tumor differentiation [92]. UCP5 (SLC25A14) inhibits mitochondrial function in colon cancer through a feedback mechanism [40]. In addition, UCP5 overexpression can reduce ROS accumulation in neurons and neuroblastoma cells [58], providing a possible therapeutic target. Energy metabolism in colorectal cancer is characterized by the dysfunction of aerobic glycolysis and mitochondrial OXPHOS [93]. SLC25A18 inhibits glycolysis and proliferation by inhibiting the Wnt/β-catenin cascade, indicating its potential application as a prognostic biomarker in patients with colon cancer [41]. It has been reported that SLC25A5 and SLC25A24 may be involved in epidermal growth factor receptor (EGFR) and extracellular regulated protein kinases (ERK)-mitogen-activated protein kinase (MAPK) signaling pathways in colon cancer and may be considered therapeutic targets [9]. SLC25A10 overexpression has been associated with reduced overall survival in patients with lung and breast cancer [47, 48]. Owing to the role of SLC25A10 in supporting redox and energy homeostasis, targeting SLC25A10 can effectively overcome the in vitro and in vivo chronic circulatory hypoxia-induced anti-death by interfering with the increase in the antioxidant capacity, thereby targeting cancer cells with tolerance to chronic circulatory hypoxia [48]. Thus, utilizing the hypoxia-induced therapy may become a new therapeutic approach [48]. SLC25A10 and SLC25A11 are involved in mitochondrial growth-stimulating hormone (GSH) transport. In HCC, SLC25A11 downregulation by siRNA mainly consumed mesh and significantly damaged the growth of HCC cells to cause hypoxia-induced ROS production and cell death, which was an adaptive mechanism of HCC and a potential new therapeutic target for HCC treatment [50]. In summary, lesions caused by abnormal mitochondrial OXPHOS are associated with the members of the SLC25 family of UCPs.

Others

Inhibition of SLC25A1 expression may be a new potential target for the treatment of most lung cancers [46]. SLC25A4 mRNA was reported to be overexpressed in acute monocytic leukemia (AML-M5), but there was no significant difference in SLC25A4 mRNA expression between patients with a complete response and those without response, suggesting that SLC25A4 may be a novel gene for acute monocytic leukemia-associated antigen [9]. ANT encoded by SLC25A4, exhibits a strong correlation with BCL2L13. This correlation is believed to facilitate the liberation of cytochrome C from the mitochondrial membrane space into the cytoplasm, thereby triggering the activation of the apoptotic caspase cascade. Furthermore, this association is considered a pivotal factor in the prognostic effects mediated by BCL2L13 in kidney cancer [94]. SLC25A4 expression was shown to be significantly associated with cancer-related fatigue in prostate cancer patients, and SLC25A4 expression was lower in proliferating cells [42]. SLC25A4 is down-regulated in gastric cancer tissues, which may be a potential therapeutic target for gastric cancer treatment [42]. The expression of SLC25A4 in Glioblastoma (GBM) is abnormal, and the carcinogenesis mechanism may be related to the loss of mitochondrial DNA (mtDNA) or multiple mtDNA. This gene may be a potential target for GBM therapy [56, 57]. SLC25A5 inhibits cell proliferation, upregulates the expression of programmed cell death-related signals, and plays its biological functions by inhibiting MAPK signaling pathway [9]. Overexpression of SLC25A5 may enhance the resistance of lung cancer cells to tyrosine kinase inhibitors and reverse the resistance of liver cancer cells to sorafenib through the phosphoinositide 3 kinase (PI3K)/Protein Kinase B (AKT) pathway [43], [44], [45]. SLC25A12 and SLC25A13 are found in humans, where SLC25A12 is upregulated in HCC cell lines and can promote cell growth, and this gene is expressed in the human liver. Its role is to provide aspartate in the cytoplasm to synthesize nucleotides, which are involved in the growth and migration of HCC cells [10, 51]. SLC25A21 as a potential target for the treatment of bladder cancer by the mechanism that SLC25A21 induces mitochondrial α-kg efflux to the cell membrane, reduces antioxidant stress, and activates ROS-mediated mitochondria-dependent apoptotic pathway to inhibit the growth of bladder cancer [55].The SLC25A43 mitochondrial transporter gene is absent in HER 2+ breast cancer, which is also commonly absent in other cancers, and altered SLC25A33 expression affects breast cancer cell proliferation [49]. In summary, the process of SLC25 family and energy metabolism is shown in Figure 1.

Figure 1: SLC25 family in PiCs, cytosolic iron, VDACs and OXPHOS: SLC25A3 encodes a PiC that transports inorganic phosphate. SLC25A7 regulates ATP synthesis to further promote the conversion of ADP to ATP through OXPHOS. PINK1–PARK2 regulates cytosolic iron through SLC25A28 and SLC25A37 transporters to inhibit pancreatic tumor growth. The interaction between VDAC1 and HK contributes to energy production while preventing apoptosis leading to cancer cell metabolism.
Figure 1:

SLC25 family in PiCs, cytosolic iron, VDACs and OXPHOS: SLC25A3 encodes a PiC that transports inorganic phosphate. SLC25A7 regulates ATP synthesis to further promote the conversion of ADP to ATP through OXPHOS. PINK1–PARK2 regulates cytosolic iron through SLC25A28 and SLC25A37 transporters to inhibit pancreatic tumor growth. The interaction between VDAC1 and HK contributes to energy production while preventing apoptosis leading to cancer cell metabolism.

Role of SLC25 in ERS

The endoplasmic reticulum is an indispensable organelle in the cell. Various stress conditions, such as hypoxia and oxidative stress, can increase the level of unfolded proteins in the endoplasmic reticulum, leading to the dissociation of receptor proteins from glucose regulated protein 78 (GRP78) on the endoplasmic reticulum membrane and activating ERS [95]. ERS maintains endoplasmic reticulum homeostasis via the normal folding of proteins, whereas persistent ERS promotes apoptosis by activating the expression of the downstream apoptotic factor C/EBP homologous protein (CHOP) [96]. CHOP is an important functional protein for ERS-induced apoptosis and a molecular marker for the activation of the ERS apoptotic pathway [97]. ERS has been reported to have a close association with UCP proteins in the SLC25 family. UCPs belong to a family of proteins in IMM that promotes OXPHOS and respiratory dissociation, enhances thermogenesis, and reduces the production of oxygen free radicals [98]. These UCPs include UCP1–6 (SLC25A7, SLC25A8, SLC25A9, SLC25A27, SLC25A14, and SLC25A30).

The activation of peroxisome prolifera-tors-activated receptors (PPARs β/δ) could potentially reverse endothelial dysfunction induced by the bacterial endotoxin LPS. This proposed mechanism involves the upregulation of UCP2, which subsequently mitigates ERS [99]. The inhibition of irisin by integrin alpha 5 (αVβ5), AMP-activated protein kinase (AMPK), or UCP2 abolished the protective effect of irisin on intestinal barrier function and reduced oxidative stress, calcium influx, and ERS after intestinal ischemia–reperfusion [6]. ERS plays an important role in resistance to arterial endothelial dysfunction in atherosclerosis. Of note, exercise reduces ERS, thereby modulating its key downstream signaling pathways, including endothelial nitric oxide synthase (eNOS), UCP2, and caspase-1 [100]. Expression of the ERS markers PKR-like endoplasmic Reticulum Kinase (PERK), eukaryotic initiation factor 2α (ELF2α), and Activating Transcription Factor 4 (ATF4) in the pancreatic tissue and the oxidative stress marker UCP2 in the liver tissue was significantly increased in diabetic rats and that isopentenol significantly improved the antioxidant status and reduced oxidative and ERS markers in the treated diabetic rats [101]. Ecklonia cava extract and pyrogalo-phloroglucinol-6, 6-bieckol can activate peroxisome proliferators (PPARγ) by attenuating ERS-mediated silencing regulatory protein type 1 (Sirt1). Subsequently, Sirt1 and PPARγ expression is reduced, leading to the restoration of UCP1 expression and the browning process in perivascular adipose tissue (PVAT) [102]. UCP4 affects storage-operated Ca2+ entry, and the depletion of ER Ca2+ stores triggers Ca2+ influx through the plasma membrane “storage-operated” channels. The stabilization of Ca2+ homeostasis and maintenance of mitochondrial function by UCP4 are associated with reduced mitochondrial ROS generation and oxidative stress; enhanced Gadd153 expression; and increased cell resistance to death [103]. Studies have shown that the circadian clock regulates metabolic homeostasis and its disturbance increases predisposition to obesity and other metabolic diseases [104]. Chronic progression phase resulted in marked changes in the gene profiles of neuropeptides, lipid metabolism, inflammation, and ERS in several metabolically related tissues, such as the hypothalamus, liver, white adipose tissue, and brown adipose tissue. The steatosis of the white adipose tissue is characterized by increased inflammation and ERS, the brown–white transformation of brown adipocytes, and decreased UCP1 expression [105]. Dextran-magnetic layered double hydroxy-fluorouracil (DMF) can induce a strong ERS effect in MGC-803 cells, and some signaling pathways related to ERS may be involved during tumorigenesis. DMF can reduce ATP, inhibit mitochondrial membrane potential (MMP), increase Ca2+, and activate UCP2 and calpain-1 in MGC-803 cells [106]. Quercetin affected transforming growth factor (TGF1), ERS, and apoptosis to prevent stromal extracellular matrix deposition in the liver fibrosis stage [107]. It slowed down cancer cell growth and spread via signaling pathways linked to Human telomerase reverse transcriptase (hTERT), mitogen-activated proteinkinase kinase 1 (MEK1)/Extracellular regulatory protein kinase (ERK1/2), Notch, and Wnt/catenin in the advanced stages of HCC [107]. Some of the above results are shown in Figure 2.

Figure 2: SLC25 family in relation to ERS: ERS activates CHOP proteins to promote apoptosis. Elevated expression of PERK, ELF2α and ATF4 in pancreatic tissues promoted SLC25A8 expression to improve inhibiting oxidant status, which in turn reduced ERS. Activation of PPARs β/δ restored bacterial endotoxin LPS-induced endothelial dysfunction through upregulation of UCP2 and subsequently alleviated ERS.
Figure 2:

SLC25 family in relation to ERS: ERS activates CHOP proteins to promote apoptosis. Elevated expression of PERK, ELF2α and ATF4 in pancreatic tissues promoted SLC25A8 expression to improve inhibiting oxidant status, which in turn reduced ERS. Activation of PPARs β/δ restored bacterial endotoxin LPS-induced endothelial dysfunction through upregulation of UCP2 and subsequently alleviated ERS.

SLC25 inhibitors

The SLC25 family has a significant influence on cancer, yet there is limited knowledge regarding its inhibitors in cancer. Consequently, we present a summary of the inhibitors of the SLC25 family in Table 3 below. Praseodymium trivalent ion (Pr3+) functions as a novel competitive inhibitor of both the human mitochondrial transporters SLC25A29 and SLC25A20 [25]. To validate the inhibitory effect of Pr3+ on SLC25A29 and SLC25A20, Experiments utilizing a mitochondrial transporter. The results indicated that Pr3+ had significant inhibitory effects on SLC25A29 and SLC25A20 at concentrations within the micromolar range. This inhibition was attributed to the coordination of Pr3+ with essential acidic residues in the matrix salt-bridge network. Furthermore, the researchers observed varying degrees of inhibition on SLC25A14, SLC25A29, SLC25A30, SLC25A33, and SLC25A36 with mercury compound inhibitors [31, 108]. SLC25A20, on the other hand, was found to be inhibited by drugs such as K+/H+-ATPase inhibitors (omeprazole) or antibiotics (β-lactams) [109]. In order to confirm the inhibition of SLC25A20 by β-lactam antibiotics, conducted an extraction and purification of SLC25A20 from rat liver mitochondria, followed by reconstitution of SLC25A20 in proteoliposomes. The findings revealed that the recombinant SLC25A20 was indeed inhibited by β-lactam antibiotics, with cefonicid proving to be the most potent inhibitor of this protein [109]. Additionally, through the utilization of proteoliposomal recombinant SLC25A20, the researchers demonstrated significant inhibition of SLC25A20 by omeprazole, employing molecular docking and sentinel mutagenesis techniques [110]. Inhibition of SLC25A13 by the posterior inferior cerebellar artery (PICA) inhibitor H89 leads to an upregulation of aspartate/glutamate carrier genes in neurodegenerative disorders [111]. Okadaic acid (OA) is a selective inhibitor of multiple serine/threonine protein phosphatases. OA induces an overexpression of SLC25A4 [112]. Overexpression of SLC25A4 triggers apoptosis in various immortalized fibroblast and tumor cell lines, with the exception of glioma cells [113]. Interestingly, previous studies have reported that the overexpression of SLC25A4 does not exhibit any association with apoptosis. Therefore, further investigation is necessary to validate this finding. The literature suggests that butylmalonic acid, benzylmalonic acid, and phenylsuccinic acid act as inhibitors of SLC25A10 [114]. Additionally, both tannic acid and bromocresol violet inhibit the activity of SLC25A18 and SLC25A22. Furthermore, Carboxyatractyloside (CATR), Atractyloside (ATR), and Bongkrekic acid (BKA) are known inhibitors of ANT [115]. Hence, it is crucial to mitigate the potential impact of abnormal expression of SLC25 family proteins on human physiology, and additional studies are needed to develop and study SLC25 family inhibitors.

Table 3:

SLC25 family inhibitors.

Author Inhibitors Target SLC25 family
2022. Incampo [25]. Pr3+ Coordination of Pr3+ with key acidic residues of the matrix salt bridge network. SLC25A20
SLC25A29
2019. Gorgoglione [108]. Pyridoxal 5′-phosphate, bathophenanthroline and the organic mercurials mersalyl, p-chloromercuribenzoate and HgCl2. Mediated [35S] sulfate/sulfate exchange reactions. SLC25A14
2014. Porcelli [116]. SLC25A29
2014. Di Noia [31]. SLC25A30
SLC25A33
SLC25A36
2015. Tonezzi [109]. K+/H+-ATPase inhibitors or antibiotics (β-lactams). Inhibits carnitine/acetylcarnitine converting enzyme. SLC25A20
2015. Menga [111]. PKA inhibitor H89. Changes in CREB signaling pathway. SLC25A12
2012. Valdiglesias [114]. Okadaic acid. Apoptosis induction. SLC25A4

SLC25 and immunity

The immune system, gradually formed over the long-term evolution of organisms, is the first line of defense against the invasion of pathogens. The immune system comprises immune organs and tissues, immune cells, and immune molecules [117]. Immune cells involved in immunity include mononuclear macrophages, dendritic cells, neutrophils, NK cells, B cells, and T cells [118]. MicroRNAs miR-302b and miR-372 exerted regulatory control over mitochondrial metabolism through the SLC25A12 transporter, consequently modulating the mitochondrial antiviral signaling (MAVS) protein-mediated antiviral innate immunity [7]. The negative correlation between CD8 and SLC25A5 in patients with colon cancer is based on bioinformatic results, requiring further experimental validation [9]. Vitamin A plays a major role in innate immunity, cell-mediated immunity, and humoral antibody immunity [119]. Its deficiency increases the type 1 helper T (Th1) response, enhances the levels of proinflammatory cytokines, elevates the expression of leptin and UCP, and promotes adipogenesis [120]. Conjugated linoleic acid (CLA) supplementation can modulate immune function, resynthesize glycogen, and enhance bone mineralization [121]. Supplementation with CLA increased lipolysis and reduced fatty acid accumulation in the adipose tissue by reducing the lipase lipoprotein activity and increasing the carnitine-palm oil-transferase-1 activity, enhancing its interaction with PPARγ, and promoting UCP1 expression [122]. UCP4 may play an important role in neuronal aging and innate immune responses via mitochondrial membrane protein mediation [123]. Immune-induced fever and hyperthermia induced by emotional stress in mice may involve UCP3-mediated muscle thermogenesis [124]. Several mechanisms have been proposed for this bidirectional communication between the immune system and the brain after sepsis. These include neuroinflammation, oxidative stress, and mitochondrial dysfunction [125]. Stanniocalcin-1 is an endogenous neuroprotective protein that exerts anti-inflammatory effects and inhibits superoxide production via the induction of UCPs in mitochondria [125]. The presence of spontaneous UCP-specific CD4 T-cell responses in non-small cell lung cancer increased survival in patients who responded to chemotherapy and facilitated the development of novel cancer immunotherapies that utilize CD4 T cells [126]. Ca2+ plays a central role in controlling mitochondrial bioenergetics in splenic lymphocytes during the immune response against cancer, and UCP2 level is significantly increased in these activated lymphocytes [127]. It has been reported that UCP1 and UCP2 play key roles in the prognosis, metabolism, and immune infiltration of breast cancer [128]. Thus, the SLC25 family proteins are closely associated with immunity. In particular, the proteins are closely associated with the UCP members of the protein family.

Conclusions

The SLC25 family plays a crucial role in regulating mitochondrial energy metabolism through various mechanisms, including PiC, cellular iron, VDACs, and OXPHOS. Specifically, dysregulation of OXPHOS has been linked primarily to UCP members of the SLC25 family. Additionally, the involvement of SLC25A8 and other related proteins has been found to effectively inhibit endoplasmic reticulum stress (ERS), while the activity of the SLC25A12 transporter is modulated by miR-302b and miR-372, thereby impacting mitochondrial metabolism and the MAVS-mediated antiviral innate immune system. Consequently, the SLC25 family assumes significant roles in organisms by influencing energy metabolism, ERS, and immune responses.

Perspectives

In summary, the SLC25 family of related proteins is closely related to tumor development, as well as an important node of tumor energy metabolism, so it is very necessary to study the SLC25 family of proteins with tumors-specific metabolic pathways, the tumor microenvironment, and tumors-targeted therapies. We should pay great attention to the therapeutic strategies of the diseases related to this protein family and try to explore representative targeted therapies in the hope of improving patient outcomes. SLC25 family proteins can regulate ERS, and the next step is to focus on exploring the relationship between the SLC25 family proteins and Epigenetics, proteomics, and histone lactylation and acetylation, in order to comprehensively understand the potential mechanisms of their dysregulation. SLC25 family proteins also play an important role in immunity, but the existing studies are still weak, and it is necessary to explore the relationship between SLC25 family proteins and the immune microenvironment, tumors’ immune escape, and immune regulation.

Corresponding authors: Pengxian Tao, MD, First Clinical Medical College, Gansu University of Chinese Medicine, Lanzhou, China; Key Laboratory of Molecular Diagnostics and Precision Medicine for Surgical Oncology in Gansu Province, Gansu Provincial Hospital, Lanzhou, China; General Surgery Clinical Medical Center, Gansu Provincial Hospital, Lanzhou, China; Cadre Ward of General Surgery Department, Gansu Provincial Hospital, Lanzhou, China; and NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor, Gansu Provincial Hospital, Lanzhou, China, Email: (P. Tao); and Hui Cai, MD, First Clinical Medical College, Gansu University of Chinese Medicine, Lanzhou, China; Key Laboratory of Molecular Diagnostics and Precision Medicine for Surgical Oncology in Gansu Province, Gansu Provincial Hospital, Lanzhou, China; General Surgery Clinical Medical Center, Gansu Provincial Hospital, Lanzhou, China; and NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor, Gansu Provincial Hospital, Lanzhou, China, Email: (H. Cai)
Guiqian Zhang and Ning Wang contributed equally to this work.

Funding source: Natural Science Foundation of Gansu Province

Award Identifier / Grant number: 22JR5RA662，20JR5RA145

Funding source: Gansu Provincial Youth Science and Technology Fund Program

Award Identifier / Grant number: 21JR7RA642

Funding source: National Health Commission Key Laboratory Master’s and Doctor’s Fund Programs

Award Identifier / Grant number: NHCDP2022010

Funding source: Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences

Award Identifier / Grant number: 21GSSYC-2

Funding source: The 2021 Central-Guided Local Science and Technology Development Fund

Award Identifier / Grant number: ZYYDDFFZZJ-1

Funding source: Key talent project of Gansu Province of the Organization Department of Gansu Provincial Party Committee

Award Identifier / Grant number: 2020RCXM076

Funding source: Key project of science and technology innovation platform fund of Gansu Provincial People’s Hospital

Award Identifier / Grant number: 21gssya-4

Funding source: Gansu Provincial People’s Hospital Excellent Master/PhD Student Incubation Program Project Fund

Award Identifier / Grant number: 22GSSYD-19

Funding source: Postdoctoral Fund of Gansu Provincial People’s Hospital

Award Identifier / Grant number: ZX-62000001-2022-055

Acknowledgments

We would like to thank Key Laboratory of Molecular Diagnostics and Precision Medicine for Surgical Oncology in Gansu Province, and General Surgery Clinical Medical Center of Gansu Provincial Hospital for their contributions.

  1. Research ethics: Not applicable.

  2. Informed consent: All authors agreed to publish this manuscript.

  3. Author contributions: GZ, PT and HC conceived the study. GZ and NW collected the relevant data. NW completed the data analysis. GZ wrote a draft. SM, ZW and HC revised the manuscript. PT and HC reviewed the paper. All authors read and approved the final manuscript.

  4. Competing interests: The authors declare no conflict of interest.

  5. Research funding: This work was supported by grants from The 2021 Central-Guided Local Science and Technology Development Fund (ZYYDDFFZZJ-1), Key talent project of Gansu Province of the Organization Department of Gansu Provincial Party Committee (2020RCXM076), Gansu Provincial Youth Science and Technology Fund Program (21JR7RA642), Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences(21GSSYC-2), Gansu Provincial People’s Hospital Excellent Master/PhD Student Incubation Program Project Fund (22GSSYD-19), Key project of science and technology innovation platform fund of Gansu Provincial People’s Hospital (21gssya-4), Natural Science Foundation of Gansu Province (22JR5RA662, 20JR5RA145), Postdoctoral Fund of Gansu Provincial People’s Hospital (ZX-62000001-2022-055), National Health Commission Key Laboratory Master’s and Doctor’s Fund Programs (NHCDP2022010).

  6. Data availability: The data presented in this study are available in the inserted articles.

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Received: 2023-07-15
Accepted: 2023-11-21
Published Online: 2023-12-06

© 2023 the author(s), published by De Gruyter, Berlin/Boston

This work is licensed under the Creative Commons Attribution 4.0 International License.

Artikel in diesem Heft

  1. Frontmatter
  2. Review Articles
  3. Advances in ferroptosis of cancer therapy
  4. Immunotherapy in hepatocellular carcinoma: an overview of immune checkpoint inhibitors, drug resistance, and adverse effects
  5. The role of matrix metalloproteinase-2 in the metastatic cascade: a review
  6. The tumor microenvironment: a key player in multidrug resistance in cancer
  7. Robotic vs. laparoscopic approach in obese patients with endometrial cancer: which is the best? A mini-review
  8. SLC25 family with energy metabolism and immunity in malignant tumors
  9. Research Articles
  10. Catalase expression is an independent prognostic marker in liver hepatocellular carcinoma
  11. A novel immune-associated prognostic signature based on the immune cell infiltration analysis for hepatocellular carcinoma
  12. AKAP12 inhibits the proliferation of ovarian cancer by activating the Hippo pathway
  13. AQP1 as a novel biomarker to predict prognosis and tumor immunity in glioma patients
  14. Exosomal circular RNA NT5E driven by heterogeneous nuclear ribonucleoprotein A1 induces temozolomide resistance by targeting microRNA-153 in glioma cells
  15. miR‐30a‐3p inhibits the proliferation of laryngeal cancer cells by targeting DNMT3a through regulating DNA methylation of PTEN
  16. Disulfidptosis-related long non-coding RNAs predict prognosis and indicate therapeutic response in non-small cell lung carcinoma
  17. Case Report
  18. Primary retroperitoneal choriocarcinoma with lung and liver metastasis in a male patient: case report
  19. Short Commentary
  20. Clinical pharmacy services in cancer patients with hypertension
https://doi.org/10.1515/oncologie-2023-0280
Schlagwörter für diesen Artikel
SLC25 family; energy metabolism; endoplasmic reticulum stress; inhibitors; immunity; cancer
Creative Commons
BY 4.0

Artikel in diesem Heft

  1. Frontmatter
  2. Review Articles
  3. Advances in ferroptosis of cancer therapy
  4. Immunotherapy in hepatocellular carcinoma: an overview of immune checkpoint inhibitors, drug resistance, and adverse effects
  5. The role of matrix metalloproteinase-2 in the metastatic cascade: a review
  6. The tumor microenvironment: a key player in multidrug resistance in cancer
  7. Robotic vs. laparoscopic approach in obese patients with endometrial cancer: which is the best? A mini-review
  8. SLC25 family with energy metabolism and immunity in malignant tumors
  9. Research Articles
  10. Catalase expression is an independent prognostic marker in liver hepatocellular carcinoma
  11. A novel immune-associated prognostic signature based on the immune cell infiltration analysis for hepatocellular carcinoma
  12. AKAP12 inhibits the proliferation of ovarian cancer by activating the Hippo pathway
  13. AQP1 as a novel biomarker to predict prognosis and tumor immunity in glioma patients
  14. Exosomal circular RNA NT5E driven by heterogeneous nuclear ribonucleoprotein A1 induces temozolomide resistance by targeting microRNA-153 in glioma cells
  15. miR‐30a‐3p inhibits the proliferation of laryngeal cancer cells by targeting DNMT3a through regulating DNA methylation of PTEN
  16. Disulfidptosis-related long non-coding RNAs predict prognosis and indicate therapeutic response in non-small cell lung carcinoma
  17. Case Report
  18. Primary retroperitoneal choriocarcinoma with lung and liver metastasis in a male patient: case report
  19. Short Commentary
  20. Clinical pharmacy services in cancer patients with hypertension
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