国际口腔医学杂志 ›› 2024, Vol. 51 ›› Issue (1): 10-20.doi: 10.7518/gjkq.2024019
Wang Miao(),Meng Wanrong,Li Longjiang()
摘要:
代谢重编程是恶性肿瘤的重要特征之一,是促使肿瘤细胞在营养匮乏的情况下存活并促进其恶性进展的重要原因。近些年研究发现,胱氨酸-谷氨酸反向转运体(system Xc-)不仅是诱导铁死亡的关键靶点,同时对肿瘤代谢起重要调控作用,该转运体是导致肿瘤细胞对葡萄糖高度依赖的原因之一,这提示对于高表达system Xc-的肿瘤,抑制葡萄糖摄取及糖代谢是一种有效的治疗策略。本文从system Xc-的表达调控、功能及其对肿瘤代谢的影响等方面进行综述,以期为抗肿瘤代谢治疗提供新思路。
中图分类号:
1 | Parker JL, Deme JC, Kolokouris D, et al. Molecular basis for redox control by the human cystine/glutamate antiporter system xc[J]. Nat Commun, 2021, 12(1): 7147. |
2 | Dixon SJ, Lemberg KM, Lamprecht MR, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death[J]. Cell, 2012, 149(5): 1060-1072. |
3 | Jiang XJ, Stockwell BR, Conrad M. Ferroptosis: mechanisms, biology and role in disease[J]. Nat Rev Mol Cell Biol, 2021, 22(4): 266-282. |
4 | Shin CS, Mishra P, Watrous JD, et al. The glutamate/cystine xCT antiporter antagonizes glutamine meta-bolism and reduces nutrient flexibility[J]. Nat Commun, 2017, 8: 15074. |
5 | Stine ZE, Walton ZE, Altman BJ, et al. MYC, metabolism, and cancer[J]. Cancer Discov, 2015, 5(10): 1024-1039. |
6 | Dey P, Kimmelman AC, DePinho RA. Metabolic codependencies in the tumor microenvironment[J]. Cancer Discov, 2021, 11(5): 1067-1081. |
7 | Liu Y, Gu W. The complexity of p53-mediated metabolic regulation in tumor suppression[J]. Semin Cancer Biol, 2022, 85: 4-32. |
8 | Liu J, Xia X, Huang P. xCT: a critical molecule that links cancer metabolism to redox signaling[J]. Mol Ther, 2020, 28(11): 2358-2366. |
9 | Abdullah M, Lee SJ. Extracellular concentration of L-cystine determines the sensitivity to system xc - inhibitors[J]. Biomol Ther, 2022, 30(2): 184-190. |
10 | Yan RH, Zhao X, Lei JL, et al. Structure of the human LAT1-4F2hc heteromeric amino acid transpor-ter complex[J]. Nature, 2019, 568(7750): 127-130. |
11 | Lewerenz J, Sato H, Albrecht P, et al. Mutation of ATF4 mediates resistance of neuronal cell lines against oxidative stress by inducing xCT expression[J]. Cell Death Differ, 2012, 19(5): 847-858. |
12 | Fan Z, Wirth AK, Chen D, et al. Nrf2-Keap1 pathway promotes cell proliferation and diminishes ferroptosis[J]. Oncogenesis, 2017, 6(8): e371. |
13 | Byles V, Cormerais Y, Kalafut K, et al. Hepatic mTORC1 signaling activates ATF4 as part of its metabolic response to feeding and insulin[J]. Mol Metab, 2021, 53: 101309. |
14 | Quirós PM, Prado MA, Zamboni N, et al. Multio-mics analysis identifies ATF4 as a key regulator of the mitochondrial stress response in mammals[J]. J Cell Biol, 2017, 216(7): 2027-2045. |
15 | Feng L, Li M, Hu X, et al. CK1δ stimulates ubiquitination-dependent proteasomal degradation of ATF4 to promote chemoresistance in gastric cancer[J]. Clin Transl Med, 2021, 11(10): e587. |
16 | Longchamp A, Mirabella T, Arduini A, et al. Amino acid restriction triggers angiogenesis via GCN2/ATF4 regulation of VEGF and H2S production[J]. Cell, 2018, 173(1): 117-129.e14. |
17 | Chang H, Cai F, Zhang Y, et al. Early-stage autophagy protects nucleus pulposus cells from glucose deprivation-induced degeneration via the p-eIF2α/ATF4 pathway[J]. Biomed Pharmacother, 2017, 89: 529-535. |
18 | Loong JH, Wong TL, Tong M, et al. Glucose deprivation-induced aberrant FUT1-mediated fucosyla-tion drives cancer stemness in hepatocellular carcinoma[J]. J Clin Invest, 2021, 131(11): e143377. |
19 | Balsa E, Soustek MS, Thomas A, et al. ER and nu-trient stress promote assembly of respiratory chain super complexes through the PERK-eIF2α axis[J]. Mol Cell, 2019, 74(5): 877-890.e6. |
20 | Ye JB, Kumanova M, Hart LS, et al. The GCN2-ATF4 pathway is critical for tumour cell survival and proliferation in response to nutrient deprivation[J]. EMBO J, 2010, 29(12): 2082-2096. |
21 | Koppula P, Zhang YL, Shi JJ, et al. The glutamate/cystine antiporter SLC7A11/xCT enhances cancer cell dependency on glucose by exporting glutamate[J]. J Biol Chem, 2017, 292(34): 14240-14249. |
22 | Sato H, Nomura S, Maebara K, et al. Transcriptio-nal control of cystine/glutamate transporter gene by amino acid deprivation[J]. Biochem Biophys Res Commun, 2004, 325(1): 109-116. |
23 | Ma Q. Role of nrf2 in oxidative stress and toxicity[J]. Annu Rev Pharmacol Toxicol, 2013, 53: 401-426. |
24 | Niture SK, Khatri R, Jaiswal AK. Regulation of Nrf2-an update[J]. Free Radic Biol Med, 2014, 66: 36-44. |
25 | Habib E, Linher-Melville K, Lin HX, et al. Expression of xCT and activity of system xc(-) are regula-ted by NRF2 in human breast cancer cells in response to oxidative stress[J]. Redox Biol, 2015, 5: 33-42. |
26 | Lim JKM, Leprivier G. The impact of oncogenic RAS on redox balance and implications for cancer development[J]. Cell Death Dis, 2019, 10(12): 955. |
27 | Lim JKM, Delaidelli A, Minaker SW, et al. Cystine/glutamate antiporter xCT (SLC7A11) facilitates oncogenic RAS transformation by preserving intracellular redox balance[J]. Proc Natl Acad Sci U S A, 2019, 116(19): 9433-9442. |
28 | Wu C, Shen Z, Lu Y, et al. p53 promotes ferroptosis in macrophages treated with Fe3O4 nanoparticles[J]. ACS Appl Mater Interfaces, 2022, 14(38): 42791-42803. |
29 | Fu DZ, Wang CX, Yu L, et al. Induction of ferroptosis by ATF3 elevation alleviates cisplatin resistance in gastric cancer by restraining Nrf2/Keap1/xCT signaling[J]. Cell Mol Biol Lett, 2021, 26(1): 26. |
30 | Wang LY, Liu YC, Du TT, et al. ATF3 promotes erastin-induced ferroptosis by suppressing system Xc[J]. Cell Death Differ, 2020, 27(2): 662-675. |
31 | Liu SJ, Trejo-Arellano MS, Qiu YC, et al. H2A ubiquitination is essential for polycomb repressive complex 1-mediated gene regulation in marchantia polymorpha[J]. Genome Biol, 2021, 22(1): 253. |
32 | Fierz B, Chatterjee C, McGinty RK, et al. Histone H2B ubiquitylation disrupts local and higher-order chromatin compaction[J]. Nat Chem Biol, 2011, 7(2): 113-119. |
33 | Zhang YL, Koppula P, Gan BY. Regulation of H2A ubiquitination and SLC7A11 expression by BAP1 and PRC1[J]. Cell Cycle, 2019, 18(8): 773-783. |
34 | Wang YF, Yang L, Zhang XJ, et al. Epigenetic regulation of ferroptosis by H2B monoubiquitination and p53[J]. EMBO Rep, 2019, 20(7): e47563. |
35 | Wu C, Cui YQ, Liu XH, et al. The RNF20/40 complex regulates p53-dependent gene transcription and mRNA splicing[J]. J Mol Cell Biol, 2020, 12(2): 113-124. |
36 | Minsky N, Oren M. The RING domain of Mdm2 mediates histone ubiquitylation and transcriptional repression[J]. Mol Cell, 2004, 16(4): 631-639. |
37 | Cole AJ, Dickson KA, Liddle C, et al. Ubiquitin chromatin remodelling after DNA damage is associa-ted with the expression of key cancer genes and pathways[J]. Cell Mol Life Sci, 2021, 78(3): 1011-1027. |
38 | Lee SY, Kim HS, Kim MJ, et al. Glutamine metabolite α-ketoglutarate acts as an epigenetic co-factor to interfere with osteoclast differentiation[J]. Bone, 2021, 145: 115836. |
39 | Sui SY, Zhang J, Xu SP, et al. Ferritinophagy is required for the induction of ferroptosis by the bromodomain protein BRD4 inhibitor (+)-JQ1 in cancer cells[J]. Cell Death Dis, 2019, 10(5): 331. |
40 | Ogiwara H, Takahashi K, Sasaki M, et al. Targeting the vulnerability of glutathione metabolism in ARID1A-deficient cancers[J]. Cancer Cell, 2019, 35(2): 177-190.e8. |
41 | Sasaki M, Chiwaki F, Kuroda T, et al. Efficacy of glutathione inhibitors for the treatment of ARID1A-deficient diffuse-type gastric cancers[J]. Biochem Biophys Res Commun, 2020, 522(2): 342-347. |
42 | Ishimoto T, Nagano O, Yae T, et al. CD44 variant regulates redox status in cancer cells by stabilizing the xCT subunit of system xc(-) and thereby promotes tumor growth[J]. Cancer Cell, 2011, 19(3): 387-400. |
43 | Yamaguchi I, Yoshimura SH, Katoh H. High cell density increases glioblastoma cell viability under glucose deprivation via degradation of the cystine/glutamate transporter xCT (SLC7A11)[J]. J Biol Chem, 2020, 295(20): 6936-6945. |
44 | Digomann D, Linge A, Dubrovska A. SLC3A2/CD98hc, autophagy and tumor radioresistance: a link confirmed[J]. Autophagy, 2019, 15(10): 1850-1851. |
45 | Digomann D, Kurth I, Tyutyunnykova A, et al. The CD98 heavy chain is a marker and regulator of head and neck squamous cell carcinoma radiosensitivity[J]. Clin Cancer Res, 2019, 25(10): 3152-3163. |
46 | Nachef M, Ali AK, Almutairi SM, et al. Targeting SLC1A5 and SLC3A2/SLC7A5 as a potential strategy to strengthen anti-tumor immunity in the tumor microenvironment[J]. Front Immunol, 2021, 12: 624324. |
47 | Park Y, Reyna-Neyra A, Philippe L, et al. mTORC1 balances cellular amino acid supply with demand for protein synthesis through post-transcriptional control of ATF4[J]. Cell Rep, 2017, 19(6): 1083-1090. |
48 | Verbist KC, Guy CS, Milasta S, et al. Metabolic maintenance of cell asymmetry following division in activated T lymphocytes[J]. Nature, 2016, 532(7599): 389-393. |
49 | Ma L, Zhang X, Yu K, et al. Targeting SLC3A2 su-bunit of system XC - is essential for m6A reader YTHDC2 to be an endogenous ferroptosis inducer in lung adenocarcinoma[J]. Free Radic Biol Med, 2021, 168: 25-43. |
50 | Zhu JJ, Berisa M, Schwörer S, et al. Transsulfuration activity can support cell growth upon extracellular cysteine limitation[J]. Cell Metab, 2019, 30(5): 865-876.e5. |
51 | Deneke SM, Fanburg BL. Regulation of cellular glutathione[J]. Am J Physiol, 1989, 257(4 Pt 1): L163-L173. |
52 | Yang WS, Stockwell BR. Ferroptosis: death by lipid peroxidation[J]. Trends Cell Biol, 2016, 26(3): 165-176. |
53 | Yagoda N, von Rechenberg M, Zaganjor E, et al. RAS-RAF-MEK-dependent oxidative cell death involving voltage-dependent anion channels[J]. Nature, 2007, 447(7146): 864-868. |
54 | Suarez-Almazor ME, Belseck E, Shea B, et al. Sulfasalazine for rheumatoid arthritis[J]. Cochrane Database Syst Rev, 2000, 1998(2): CD000958. |
55 | Yuk H, Abdullah M, Kim DH, et al. Necrostatin-1 prevents ferroptosis in a RIPK1- and IDO-independent manner in hepatocellular carcinoma[J]. Antioxidants (Basel), 2021, 10(9): 1347. |
56 | Ju HQ, Lin JF, Tian T, et al. NADPH homeostasis in cancer: functions, mechanisms and therapeutic implications[J]. Signal Transduct Target Ther, 2020, 5(1): 231. |
57 | Ying MF, You D, Zhu XB, et al. Lactate and glutamine support NADPH generation in cancer cells under glucose deprived conditions[J]. Redox Biol, 2021, 46: 102065. |
58 | Liu XG, Olszewski K, Zhang YL, et al. Cystine transporter regulation of pentose phosphate pathway dependency and disulfide stress exposes a targetable metabolic vulnerability in cancer[J]. Nat Cell Biol, 2020, 22(4): 476-486. |
59 | Liu XG, Nie LT, Zhang YL, et al. Actin cytoskeleton vulnerability to disulfide stress mediates disulfidptosis[J]. Nat Cell Biol, 2023, 25(3): 404-414. |
60 | Richtsmeier WJ, Dauchy R, Sauer LA. In vivo nu-trient uptake by head and neck cancers[J]. Cancer Res, 1987, 47(19): 5230-5233. |
61 | Kodama M, Oshikawa K, Shimizu H, et al. A shift in glutamine nitrogen metabolism contributes to the malignant progression of cancer[J]. Nat Commun, 2020, 11(1): 1320. |
62 | Ji XM, Qian J, Rahman SMJ, et al. xCT (SLC7A11)-mediated metabolic reprogramming promotes non-small cell lung cancer progression[J]. Oncogene, 2018, 37(36): 5007-5019. |
63 | Romero R, Sayin VI, Davidson SM, et al. Keap1 loss promotes Kras-driven lung cancer and results in dependence on glutaminolysis[J]. Nat Med, 2017, 23(11): 1362-1368. |
64 | Okazaki S, Umene K, Yamasaki J, et al. Glutaminoly-sis-related genes determine sensitivity to xCT-targe-ted therapy in head and neck squamous cell carcinoma[J]. Cancer Sci, 2019, 110(11): 3453-3463. |
65 | Muir A, Danai LV, Gui DY, et al. Environmental cystine drives glutamine anaplerosis and sensitizes cancer cells to glutaminase inhibition[J]. Elife, 2017, 6: e27713. |
66 | Ganapathy-Kanniappan S, Geschwind JF. Tumor glycolysis as a target for cancer therapy: progress and prospects[J]. Mol Cancer, 2013, 12: 152. |
67 | Wang HZ, Nicolay BN, Chick JM, et al. The metabolic function of cyclin D3-CDK6 kinase in cancer cell survival[J]. Nature, 2017, 546(7658): 426-430. |
68 | Koppula P, Zhang YL, Zhuang L, et al. Amino acid transporter SLC7A11/xCT at the crossroads of regulating redox homeostasis and nutrient dependency of cancer[J]. Cancer Commun (Lond), 2018, 38(1): 12. |
69 | Koppula P, Zhuang L, Gan BY. Cystine transporter SLC7A11/xCT in cancer: ferroptosis, nutrient dependency, and cancer therapy[J]. Protein Cell, 2021, 12(8): 599-620. |
70 | Lee Y, Itahana Y, Ong CC, et al. Redox-dependent AMPK inactivation disrupts metabolic adaptation to glucose starvation in xCT-overexpressing cancer cells[J]. J Cell Sci, 2022, 135(15): jcs259090. |
71 | Goji T, Takahara K, Negishi M, et al. Cystine uptake through the cystine/glutamate antiporter xCT triggers glioblastoma cell death under glucose deprivation[J]. J Biol Chem, 2017, 292(48): 19721-19732. |
72 | Hsieh CH, Lin YJ, Chen WL, et al. HIF-1α triggers long-lasting glutamate excitotoxicity via system xc - in cerebral ischaemia-reperfusion[J]. J Pathol, 2017, 241(3): 337-349. |
73 |
Wang M, Li B, Meng W, et al. System Xc- exacerbates metabolic stress under glucose depletion in oral squamous cell carcinoma[J]. Oral Dis, 2023. doi: 10.1111/odi.14774 .
doi: 10.1111/odi.14774 |
74 | Murphy TA, Dang CV, Young JD. Isotopically nonstationary 13C flux analysis of Myc-induced metabo-lic reprogramming in B-cells[J]. Metab Eng, 2013, 15: 206-217. |
75 | Jiang QK, Lu SR, Xu XL, et al. Inhibition of alanine-serine-cysteine transporter 2-mediated auto-enhanced photodynamic cancer therapy of co-nanoassembly between V-9302 and photosensitizer[J]. J Colloid Interface Sci, 2023, 629(Pt B): 773-784. |
76 | Elgogary A, Xu QG, Poore B, et al. Combination therapy with BPTES nanoparticles and metformin targets the metabolic heterogeneity of pancreatic cancer[J]. Proc Natl Acad Sci U S A, 2016, 113(36): E5328-E5336. |
77 | Xu YY, Yu ZG, Fu H, et al. Dual inhibitions on glucose/glutamine metabolisms for nontoxic pancreatic cancer therapy[J]. ACS Appl Mater Interfaces, 2022, 14(19): 21836-21847. |
78 | Zhang M, Liu QY, Zhang MX, et al. Enhanced antitumor effects of follicle-stimulating hormone receptor-mediated hexokinase-2 depletion on ovarian cancer mediated by a shift in glucose metabolism[J]. J Nanobiotechnology, 2020, 18(1): 161. |
79 | Xu CJ, Yang HL, Xiao ZH, et al. Reduction-responsive dehydroepiandrosterone prodrug nanoparticles loaded with camptothecin for cancer therapy by enhancing oxidation therapy and cell replication inhibition[J]. Int J Pharm, 2021, 603: 120671. |
80 | Abolhasani A, Biria D, Abolhasani H, et al. Investigation of the role of glucose decorated chitosan and PLGA nanoparticles as blocking agents to glucose transporters of tumor cells[J]. Int J Nanomedicine, 2019, 14: 9535-9546. |
81 | Fu LH, Qi C, Lin J, et al. Catalytic chemistry of glucose oxidase in cancer diagnosis and treatment[J]. Chem Soc Rev, 2018, 47(17): 6454-6472. |
82 | Fu LH, Hu YR, Qi C, et al. Biodegradable manganese-doped calcium phosphate nanotheranostics for traceable cascade reaction-enhanced anti-tumor the-rapy[J]. ACS Nano, 2019, 13(12): 13985-13994. |
83 | Li R, Ng TSC, Wang SJ, et al. Therapeutically reprogrammed nutrient signalling enhances nanoparticulate albumin bound drug uptake and efficacy in KRAS-mutant cancer[J]. Nat Nanotechnol, 2021, 16(7): 830-839. |
84 | Wu ZR, Lim HK, Tan SJ, et al. Potent-by-design: amino acids mimicking porous nanotherapeutics with intrinsic anticancer targeting properties[J]. Small, 2020, 16(34): e2003757. |
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