葡萄糖-6-磷酸脱氢酶在肿瘤中作用的研究进展

doi:10.12114/j.issn.1007-9572.2021.01.404

摘要/Abstract

摘要： 肿瘤的发生是一个复杂的动态过程，能量及代谢的改变是肿瘤的基本特征之一。代谢的重新编程满足了肿瘤细胞快速增殖的能量及生物合成需求。以葡萄糖-6-磷酸脱氢酶（G6PD）为限速酶的磷酸戊糖途径（PPP）是葡萄糖代谢的重要分支之一，并在肿瘤的核苷酸、脂质等生物的合成及维持氧化还原的动态平衡中起着至关重要的作用，但对G6PD在肿瘤中作用的总结和认识还有待进一步加强。本文通过总结肿瘤中G6PD主要参与的代谢改变及与G6PD表达、活性相关的信号通路的研究成果，发现靶向G6PD不仅可以抑制肿瘤细胞的快速发展，还能增强肿瘤对其他化疗药物及放疗的敏感性。

关键词: 肿瘤, 葡萄糖-6-磷酸脱氢酶, 磷酸戊糖途径, 核糖-5-磷酸, NADPH, ROS, 综述

Abstract: Tumorigenesis is a dynamic and complex progress． The change in energy and metabolism is one of the basic characteristics of the tumor. Metabolic reprogramming meets the needs of energy and biosynthesis of rapidly proliferated tumor cells. The pentose phosphate pathway（PPP）with glucose-6-phosphate dehydrogenase（G6PD）as the rate-limiting enzyme is an important branch of glucose metabolism，and play a vital role in the synthesis of nucleotides，lipids，and other biomolecules and the maintenance of redox homeostasis. However，our understanding of the role of G6PD in tumors needs to be further strengthened. We reviewed the metabolic changes and signal pathways associated with the expression and activity of G6PD in tumors，and found that targeting G6PD could not only inhibit the rapid development of tumor but also could enhance the sensitivity of tumors to other chemotherapeutics and radiotherapy.

Key words: Tumor, Glucose-6-phosphate dehydrogenase, Pentose phosphate pathway, Ribose-5-phosphate, NADPH, ROS, Review

孙键,毛星星,龙圆圆,等. 葡萄糖-6-磷酸脱氢酶在肿瘤中作用的研究进展[J]. 中国全科医学, 2021, 24(35): 4540-4548. DOI: 10.12114/j.issn.1007-9572.2021.01.404.
SUN Jian,MAO Xingxing,LONG Yuanyuan, et al. Research Progresses on the Role of Glucose-6-phosphate Dehydrogenase in Tumors　[J]. Chinese General Practice, 2021, 24(35): 4540-4548. DOI: 10.12114/j.issn.1007-9572.2021.01.404.

参考文献

［1］LONGO L，VANEGAS O C，PATEL M，et al. Maternally transmitted severe glucose 6-phosphate dehydrogenase deficiency is an embryonic lethal［J］. EMBO J，2002，21（16）：4229-4239. DOI：10.1093/emboj/cdf426.
［2］YANG H C，CHEN T L，WU Y H，et al. Glucose 6-phosphate dehydrogenase deficiency enhances germ cell apoptosis and causes defective embryogenesis in Caenorhabditis elegans［J］. Cell Death Dis，2013，4：e616. DOI：10.1038/cddis.2013.132.
［3］TIAN W N，BRAUNSTEIN L D，PANG J，et al. Importance of glucose-6-phosphate dehydrogenase activity for cell growth［J］. J Biol Chem，1998，273（17）：10609-10617. DOI：10.1074/jbc.273.17.10609.
［4］NóBREGA-PEREIRA S，FERNANDEZ-MARCOS P J，BRIOCHE T，et al. G6PD protects from oxidative damage and improves healthspan in mice［J］. Nat Commun，2016，7：10894. DOI：10.1038/ncomms10894.
［5］YANG H C，WU Y H，YEN W C，et al. The redox role of G6PD in cell growth，cell death，and cancer［J］. Cells，2019，8（9）：1055. DOI：10.3390/cells8091055.
［6］HANAHAN D，WEINBERG R A. Hallmarks of cancer：the next generation［J］. Cell，2011，144（5）：646-674. DOI：10.1016/j.cell.2011.02.013.
［7］GATENBY R A，GILLIES R J. Why do cancers have high aerobic glycolysis?［J］. Nat Rev Cancer，2004，4（11）：891-899. DOI：10.1038/nrc1478.
［8］WELLEN K E，HATZIVASSILIOU G，SACHDEVA U M，et al. ATP-citrate lyase links cellular metabolism to histone acetylation［J］. Science，2009，324（5930）：1076-1080. DOI：10.1126/science.1164097.
［9］FAUBERT B，SOLMONSON A，DEBERARDINIS R. Metabolic reprogramming and cancer progression［J］. Science，2020，368（6487）：eaaw5473. DOI：10.1126/science.aaw5473.
［10］WARBURG O. On the origin of cancer cells［J］. Science，1956，123（3191）：309-314. DOI：10.1126/science.123.3191.309.
［11］JIANG P，DU W J，WU M. Regulation of the pentose phosphate pathway in cancer［J］. Protein Cell，2014，5（8）：592-602. DOI：10.1007/s13238-014-0082-8.
［12］HASHEMY S I，UNGERSTEDT J S，ZAHEDI AVVAL F，et al. Motexafin gadolinium，a tumor-selective drug targeting thioredoxin reductase and ribonucleotide reductase［J］. J Biol Chem，2006，281（16）：10691-10697. DOI：10.1074/jbc.M511373200.
［13］GANDIN V，FERNANDES A P，RIGOBELLO M P，et al. Cancer cell death induced by phosphine gold（I）compounds targeting thioredoxin reductase［J］. Biochem Pharmacol，2010，79（2）：90-101. DOI：10.1016/j. bcp. 2009.07.023.
［14］LESCHELLE X，DELPAL S，GOUBERN M，et al. Butyrate metabolism upstream and downstream acetyl-CoA synthesis and growth control of human colon carcinoma cells［J］. Eur J Biochem，2000，267（21）：6435-6442. DOI：10.1046/j.1432-1327.2000.01731.x.
［15］HAYES J D，DINKOVA-KOSTOVA A T，TEW K D. Oxidative stress in cancer［J］. Cancer Cell，2020，38（2）：167-197. DOI：10.1016/j.ccell.2020.06.001.
［16］HOLMSTR?M K M，FINKEL T. Cellular mechanisms and physiological consequences of redox-dependent signalling［J］. Nat Rev Mol Cell Biol，2014，15（6）：411-421. DOI：10.1038/nrm3801.
［17］WELLS P G，BHULLER Y，CHEN C S，et al. Molecular and biochemical mechanisms in teratogenesis involving reactive oxygen species［J］. Toxicol Appl Pharmacol，2005，207（2 suppl）：354-366. DOI：10.1016/j.taap.2005.01.061.
［18］SABHARWAL S S，SCHUMACKER P T. Mitochondrial ROS in cancer：initiators，amplifiers or an Achilles&apos；heel?［J］. Nat Rev Cancer，2014，14（11）：709-721. DOI：10.1038/nrc3803.
［19］GORRINI C，HARRIS I S，MAK T W. Modulation of oxidative stress as an anticancer strategy［J］. Nat Rev Drug Discov，2013，12（12）：931-947. DOI：10.1038/nrd4002.
［20］GOURLAY C W，AYSCOUGH K R. The actin cytoskeleton：a key regulator of apoptosis and ageing?［J］. Nat Rev Mol Cell Biol，2005，6（7）：583-589. DOI：10.1038/nrm1682.
［21］KRYSKO D V，GARG A D，KACZMAREK A，et al. Immunogenic cell death and DAMPs in cancer therapy［J］. Nat Rev Cancer，2012，12（12）：860-875. DOI：10.1038/nrc3380.
［22］STOCKWELL B R，FRIEDMANN ANGELI J P，BAYIR H，et al. Ferroptosis：a regulated cell death Nexus linking metabolism，redox biology，and disease［J］. Cell，2017，171（2）：273-285. DOI：10.1016/j.cell.2017.09.021.
［23］O'SHEA J J，HOLLAND S M，STAUDT L M. JAKs and STATs in immunity，immunodeficiency，and cancer［J］. N Engl J Med，2013，368（2）：161-170. DOI：10.1056/NEJMra1202117.
［24］BROMBERG J. Stat proteins and oncogenesis［J］. J Clin Invest，2002，109（9）：1139-1142. DOI：10.1172/jci15617.
［25］HU T，ZHANG C，TANG Q，et al. Variant G6PD levels promote tumor cell proliferation or apoptosis via the STAT3/5 pathway in the human melanoma xenograft mouse model［J］. BMC Cancer，2013，13：251. DOI：10.1186/1471-2407-13-251.
［26］ZHANG Q，YANG Z，HAN Q Q，et al. G6PD promotes renal cell carcinoma proliferation through positive feedback regulation of p-STAT3［J］. Oncotarget，2017，8（65）：109043-109060. DOI：10.18632/oncotarget. 22566.
［27］LI L，LI L，LI W，et al. TAp73-induced phosphofructokinase-1 transcription promotes the Warburg effect and enhances cell proliferation［J］. Nat Commun，2018，9（1）：4683. DOI：10.1038/s41467-018-07127-8.
［28］AGOSTINI M，ANNICCHIARICO-PETRUZZELLI M，MELINO G，et al. Metabolic pathways regulated by TAp73 in response to oxidative stress［J］. Oncotarget，2016，7（21）：29881-29900. DOI：10.18632/oncotarget.8935.
［29］JIANG P，DU W J，YANG X L. A critical role of glucose-6-phosphate dehydrogenase in TAp73-mediated cell proliferation［J］. Cell Cycle，2013，12（24）：3720-3726. DOI：10.4161/cc.27267.
［30］DU W，JIANG P，MANCUSO A，et al. TAp73 enhances the pentose phosphate pathway and supports cell proliferation［J］. Nat Cell Biol，2013，15（8）：991-1000. DOI：10.1038/ncb2789.
［31］WANG X L，WU G，CAO G X，et al. Zoledronic acid inhibits the pentose phosphate pathway through attenuating the Ras-TAp73-G6PD axis in bladder cancer cells［J］. Mol Med Rep，2015，12（3）：4620-4625. DOI：10.3892/mmr.2015.3995.
［32］GHERGUROVICH J M，ESPOSITO M，CHEN Z H，et al. Glucose-6-phosphate dehydrogenase is not essential for K-ras-driven tumor growth or metastasis［J］. Cancer Res，2020，80（18）：3820-3829. DOI：10.1158/0008-5472.CAN-19-2486.
［33］BALUAPURI A，WOLF E，EILERS M. Target gene-independent functions of MYC oncoproteins［J］. Nat Rev Mol Cell Biol，2020，21（5）：255-267. DOI：10.1038/s41580-020-0215-2.
［34］YIN X，TANG B，LI J H，et al. ID1 promotes hepatocellular carcinoma proliferation and confers chemoresistance to oxaliplatin by activating pentose phosphate pathway［J］. J Exp Clin Cancer Res，2017，36（1）：166. DOI：10.1186/s13046-017-0637-7.
［35］YANG X C，YE H H，HE M Q，et al. LncRNA PDIA3P interacts with c-Myc to regulate cell proliferation via induction of pentose phosphate pathway in multiple myeloma［J］. Biochem Biophys Res Commun，2018，498（1）：207-213. DOI：10.1016/j.bbrc.2018.02.211.
［36］HANKER A B，KAKLAMANI V，ARTEAGA C L. Challenges for the clinical development of PI3K inhibitors：strategies to improve their impact in solid tumors［J］. Cancer Discov，2019，9（4）：482-491. DOI：10.1158/2159-8290.CD-18-1175.
［37］SUN Y，GU X，ZHANG E，et al. Estradiol promotes pentose phosphate pathway addiction and cell survival via reactivation of Akt in mTORC1 hyperactive cells［J］. Cell Death Dis，2014，5：e1231. DOI：10.1038/cddis.2014.204.
［38］CHENG J，HUANG Y，ZHANG X，et al. TRIM21 and PHLDA3 negatively regulate the crosstalk between the PI3K/AKT pathway and PPP metabolism［J］. Nat Commun，2020，11（1）：1880. DOI：10.1038/s41467-020-15819-3.
［39］HONG X H，SONG R P，SONG H W，et al. PTEN antagonises Tcl1/hnRNPK-mediated G6PD pre-mRNA splicing which contributes to hepatocarcinogenesis［J］. Gut，2014，63（10）：1635-1647. DOI：10.1136/gutjnl-2013-305302.
［40］ROJO D L V M，CHAPMAN E，ZHANG D D. NRF2 and the hallmarks of cancer［J］. Cancer Cell，2018，34（1）：21-43. DOI：10.1016/j.ccell.2018.03.022.
［41］ZHANG H S，ZHANG Z G，DU G Y，et al. Nrf2 promotes breast cancer cell migration via up-regulation of G6PD/HIF-1α/Notch1 axis［J］. J Cell Mol Med，2019，23（5）：3451-3463. DOI：10.1111/jcmm.14241.
［42］SAMATIWAT P，PRAWAN A，SENGGUNPRAI L，et al. Nrf2 inhibition sensitizes cholangiocarcinoma cells to cytotoxic and antiproliferative activities of chemotherapeutic agents［J］. Tumour Biol，2016，37（8）：11495-11507. DOI：10.1007/s13277-016-5015-0.
［43］AHMAD F，DIXIT D，SHARMA V，et al. Nrf2-driven TERT regulates pentose phosphate pathway in glioblastoma［J］. Cell Death Dis，2016，7：e2213. DOI：10.1038/cddis.2016.117.
［44］KIM N W，PIATYSZEK M A，PROWSE K R，et al. Specific association of human telomerase activity with immortal cells and cancer［J］. Science，1994，266（5193）：2011-2015. DOI：10.1126/science.7605428.
［45］PONNUSAMY L，NATARAJAN S R，THANGARAJ K，et al. Therapeutic aspects of AMPK in breast cancer：progress，challenges，and future directions［J］. Biochim Biophys Acta Rev Cancer，2020，1874（1）：188379. DOI：10.1016/j.bbcan.2020.188379.
［46］YANG L，HE Z H，YAO J Y，et al. Regulation of AMPK-related glycolipid metabolism imbalances redox homeostasis and inhibits anchorage independent growth in human breast cancer cells［J］. Redox Biol，2018，17：180-191. DOI：10.1016/j.redox.2018.04.016.
［47］SHAN C L，LU Z L，LI Z，et al. 4-hydroxyphenylpyruvate dioxygenase promotes lung cancer growth via pentose phosphate pathway（PPP）flux mediated by LKB1-AMPK/HDAC10/G6PD axis［J］. Cell Death Dis，2019，10（7）：525. DOI：10.1038/s41419-019-1756-1.
［48］HU T，CHANG Y F，XIAO Z，et al. miR-1 inhibits progression of high-risk papillomavirus-associated human cervical cancer by targeting G6PD［J］. Oncotarget，2016，7（52）：86103-86116. DOI：10.18632/oncotarget.13344.
［49］BARAJAS J M，REYES R，GUERRERO M J，et al. The role of miR-122 in the dysregulation of glucose-6-phosphate dehydrogenase（G6PD）expression in hepatocellular cancer［J］. Sci Rep，2018，8（1）：9105. DOI：10.1038/s41598-018-27358-5.
［50］SU X Y，GAO C C，FENG X Y，et al. miR-613 suppresses migration and invasion in esophageal squamous cell carcinoma via the targeting of G6PD［J］. Exp Ther Med，2020，19（4）：3081-3089. DOI：10.3892/etm. 2020.8540.
［51］GUO Q，REN X，ZHAO C，et al. MicroRNA-206 inhibits tumor metastasis of nasopharyngeal carcinoma through targeting G6PD［J］. J Biol Regul Homeost Agents，2020，34（2）. DOI：10.23812/20-36A.
［52］CUI J P，PAN Y H，WANG J H，et al. MicroRNA-206 suppresses proliferation and predicts poor prognosis of HR-HPV-positive cervical cancer cells by targeting G6PD［J］. Oncol Lett，2018，16
（5）：5946-5952. DOI：10.3892/ol.2018.9326.
［53］WANG X L，CHEN K F，ZHAO Z J. LncRNA OR3A4 regulated the growth of osteosarcoma cells by modulating the miR-1207-5p/G6PD signaling［J］. Onco Targets Ther，2020，13：3117-3128. DOI：10.2147/OTT.S234514.
［54］ZHAO L，ZHANG X D，SHI Y T，et al. LncRNA SNHG14 contributes to the progression of NSCLC through miR-206/G6PD pathway［J］. Thorac Cancer，2020，11（5）：1202-1210. DOI：10.1111/1759-7714.13374.
［55］FENG J L，YANG M Q，WEI Q，et al. Novel evidence for oncogenic PiRNA-823 as a promising prognostic biomarker and a potential therapeutic target in colorectal cancer［J］. J Cell Mol Med，2020，24（16）：9028-9040. DOI：10.1111/jcmm.15537.
［56］YANG C A，HUANG H Y，LIN C L，et al. G6PD as a predictive marker for glioma risk，prognosis and chemosensitivity［J］. J Neurooncol，2018，139（3）：661-670. DOI：10.1007/s11060-018-2911-8.
［57］ZHANG R W，TAO F Z，RUAN S H，et al. The TGFβ1-FOXM1-HMGA1-TGFβ1 positive feedback loop increases the cisplatin resistance of non-small cell lung cancer by inducing G6PD expression［J］. Am J Transl Res，2019，11（11）：6860-6876.
［58］BENITO A，POLAT I H，NOéV，et al. Glucose-6-phosphate dehydrogenase and transketolase modulate breast cancer cell metabolic reprogramming and correlate with poor patient outcome［J］. Oncotarget，2017，8（63）：106693-106706. DOI：10.18632/oncotarget.21601.
［59］MELE L，LA NOCE M，PAINO F，et al. Glucose-6-phosphate dehydrogenase blockade potentiates tyrosine kinase inhibitor effect on breast cancer cells through autophagy perturbation［J］. J Exp Clin Cancer Res，2019，38（1）：160. DOI：10.1186/s13046-019-1164-5.
［60］WANG W J，CAI Q Y，ZHOU F，et al. Impaired pentose phosphate pathway in the development of 3D MCF-7 cells mediated intracellular redox disturbance and multi-cellular resistance without drug induction［J］. Redox Biol，2018，15：253-265. DOI：10.1016/j.redox.2017.12.009.
［61］WANG X，LIU H T，ZHANG X Q，et al. G6PD downregulation triggered growth inhibition and induced apoptosis by regulating STAT3 signaling pathway in esophageal squamous cell carcinoma［J］. Tumour Biol，2016，37（1）：781-789. DOI：10.1007/s13277-015-3861-9.
［62］LU M，LU L，DONG Q Z，et al. Elevated G6PD expression contributes to migration and invasion of hepatocellular carcinoma cells by inducing epithelial-mesenchymal transition［J］. Acta Biochim Biophys Sin（Shanghai），2018，50（4）：370-380. DOI：10.1093/abbs/gmy009.
［63］JU H Q，LU Y X，WU Q N，et al. Disrupting G6PD-mediated Redox homeostasis enhances chemosensitivity in colorectal cancer［J］. Oncogene，2017，36（45）：6282-6292. DOI：10.1038/onc.2017.227.
［64］FENG Q，LI X R，SUN W J，et al. Targeting G6PD reverses paclitaxel resistance in ovarian cancer by suppressing GSTP1［J］. Biochem Pharmacol，2020，178：114092. DOI：10.1016/j.bcp.2020.114092.
［65］ZHANG Q，HAN Q Q，YANG Z，et al. G6PD facilitates clear cell renal cell carcinoma invasion by enhancing MMP2 expression through ROS MAPK axis pathway［J］. Int J Oncol，2020，57（1）：197-212. DOI：10.3892/ijo. 2020. 5041.
［66］CHEN X Y，XU Z J，ZHU Z J，et al. Modulation of G6PD affects bladder cancer via ROS accumulation and the AKT pathway in vitro［J］. Int J Oncol，2018，53（4）：1703-1712. DOI：10.3892/ijo.2018.4501.
［67］CAI T C，KUANG Y M，ZHANG C H，et al. Glucose-6-phosphate dehydrogenase and NADPH oxidase 4 control STAT3 activity in melanoma cells through a pathway involving reactive oxygen species，c-SRC and SHP2［J］. Am J Cancer Res，2015，5（5）：1610-1620.
［68］COHEN P，ROSEMEYER M A. Subunit interactions of glucose-6-phosphate dehydrogenase from human erythrocytes［J］. Eur J Biochem，1969，8（1）：8-15. DOI：10.1111/j. 1432-1033. 1969. tb00488. x.
［69］HAFNER A，BULYK M L，JAMBHEKAR A，et al. The multiple mechanisms that regulate p53 activity and cell fate［J］. Nat Rev Mol Cell Biol，2019，20（4）：199-210. DOI：10.1038/s41580-019-0110-x.
［70］JIANG P，DU W J，WANG X W，et al. p53 regulates biosynthesis through direct inactivation of glucose-6-phosphate dehydrogenase［J］. Nat Cell Biol，2011，13（3）：310-316. DOI：10.1038/ncb2172.
［71］MURRAY B W，GUO C，PIRAINO J，et al. Small-molecule p21-activated kinase inhibitor PF-3758309 is a potent inhibitor of oncogenic signaling and tumor growth［J］. PNAS，2010，107（20）：9446-9451. DOI：10.1073/pnas. 0911863107.
［72］ZHANG X M，ZHANG X，LI Y，et al. PAK4 regulates G6PD activity by p53 degradation involving colon cancer cell growth［J］. Cell Death Dis，2017，8（5）：e2820. DOI：10.1038/cddis. 2017. 85.
［73］WEI J，YANG Y，LU M，et al. Escape，or vanish：control the fate of p53 through MDM2-mediated ubiquitination［J］. Anticancer Agents Med Chem，2015，16（2）：174-189. DOI：10.2174/1871520615666150907093358.
［74］KONG D H，LI S，DU Z X，et al. BAG3 elevation inhibits cell proliferation via direct interaction with G6PD in hepatocellular carcinomas［J］. Oncotarget，2016，7（1）：700-711. DOI：10.18632/oncotarget. 6396.
［75］CHEN L，YANG H X，YI Z H，et al. LncRNA GAS5 regulates redox balance and dysregulates the cell cycle and apoptosis in malignant melanoma cells［J］. J Cancer Res Clin Oncol，2019，145（3）：637-652. DOI：10.1007/s00432-018-2820-4.
［76］MA X Y，WANG L，HUANG D，et al. Polo-like kinase 1 coordinates biosynthesis during cell cycle progression by directly activating pentose phosphate pathway［J］. Nat Commun，2017，8（1）：1506. DOI：10.1038/s41467-017-01647-5.
［77］XU S N，WANG T S，LI X，et al. SIRT2 activates G6PD to enhance NADPH production and promote leukaemia cell proliferation［J］. Sci Rep，2016，6：32734. DOI：10.1038/srep32734.
［78］YE H X，HUANG H G，CAO F，et al. HSPB1 enhances SIRT2-mediated G6PD activation and promotes glioma cell proliferation［J］. PLoS One，2016，11（10）：e0164285. DOI：10.1371/journal. pone.0164285.
［79］AI G Q，DACHINENI R，KUMAR D R，et al. Aspirin inhibits glucose 6 phosphate dehydrogenase activity in HCT 116 cells through acetylation：Identification of aspirin-acetylated sites［J］. Mol Med Rep，2016，14（2）：1726-1732. DOI：10.3892/mmr.2016.5449.
［80］RAO X J，DUAN X T，MAO W M，et al. O-GlcNAcylation of G6PD promotes the pentose phosphate pathway and tumor growth［J］. Nat Commun，2015，6：8468. DOI：10.1038/ncomms9468.
［81］SALVIOLI S，STORCI G，PINTI M，et al. Apoptosis-resistant phenotype in HL-60-derived cells HCW-2 is related to changes in expression of stress-induced proteins that impact on redox status and mitochondrial metabolism［J］. Cell Death Differ，2003，10（2）：163-174. DOI：10.1038/sj.cdd.4401124.
［82］DODSON M，DARLEY-USMAR V，ZHANG J H. Cellular metabolic and autophagic pathways：traffic control by redox signaling［J］. Free Radic Biol Med，2013，63：207-221. DOI：10.1016/j.freeradbiomed.2013.05.014.
［83］BADGLEY M A，KREMER D M，MAURER H C，et al. Cysteine depletion induces pancreatic tumor ferroptosis in mice［J］. Science，2020，368（6486）：85-89. DOI：10.1126/science.aaw9872.
［84］DING C C，ROSE J，SUN T，et al. MESH1 is a cytosolic NADPH phosphatase that regulates ferroptosis［J］. Nat Metab，2020，2（3）：270-277. DOI：10.1038/s42255-020-0181-1.
［85］BUDIHARDJO，I I，WALKER D L，SVINGEN P A，et al. 6-Aminonicotinamide sensitizes human tumor cell lines to cisplatin［J］. Clin Cancer Res，1998，4（1）：117-130.
［86］POLIMENI M，VOENA C，KOPECKA J，et al. Modulation of doxorubicin resistance by the glucose-6-phosphate dehydrogenase activity［J］. Biochem J，2011，439（1）：141-149. DOI：10.1042/BJ20102016.
［87］RATKO T A，DETRISAC C J，MEHTA R G，et al. Inhibition of rat mammary gland chemical carcinogenesis by dietary dehydroepiandrosterone or a fluorinated analogue of dehydroepiandrosterone［J］. Cancer Res，1991，51（2）：481-486.
［88］RAO K，JOHNSON W，BOSLAND M，et al. Chemoprevention of rat prostate carcinogenesis by early and delayed administration of dehydroepiandrosterone［J］. Cancer Res，1999，59（13）：3084-3089.
［89］INANO H，ISHII-OHBA H，SUZUKI K，et al. Chemoprevention by dietary dehydroepiandrosterone against promotion/progression phase of radiation-induced mammary tumorigenesis in rats［J］. J Steroid Biochem Mol Biol，1995，54（1/2）：47-53. DOI：10.1016/0960-0760（95）00113-E.
［90］SHOHAT-TAL A，SEN A，BARAD D H，et al. Genetics of androgen metabolism in women with infertility and hypoandrogenism［J］. Nat Rev Endocrinol，2015，11（7）：429-441. DOI：10.1038/nrendo.2015.64.
［91］SHIN E S，PARK J，SHIN J M，et al. Catechin gallates are NADP+-competitive inhibitors of glucose-6-phosphate dehydrogenase and other enzymes that employ NADP+as a coenzyme［J］. Bioorg Med Chem，2008，16（7）：3580-3586. DOI：10.1016/j.bmc.2008.02.030.
［92］MELE L，PAINO F，PAPACCIO F，et al. A new inhibitor of glucose-6-phosphate dehydrogenase blocks pentose phosphate pathway and suppresses malignant proliferation and metastasis in vivo［J］. Cell Death Dis，2018，9（5）：572. DOI：10.1038/s41419-018-0635-5.
［93］FRIESEN C，KIESS Y，DEBATIN K M. A critical role of glutathione in determining apoptosis sensitivity and resistance in leukemia cells［J］. Cell Death Differ，2004，11（Suppl 1）：S73-S85. DOI：10.1038/sj.cdd.4401431.
［94］GESSNER T，VAUGHAN L A，BEEHLER B C，et al. Elevated pentose cycle and glucuronyltransferase in daunorubicin-resistant P388 cells［J］. Cancer Res，1990，50（13）：3921-3927.
［95］TUTTLE S，STAMATO T，PEREZ M L，et al. Glucose-6-phosphate dehydrogenase and the oxidative pentose phosphate cycle protect cells against apoptosis induced by low doses of ionizing radiation［J］. Radiat Res，2000，153（6）：781-787. DOI：10.1667/0033-7587(2000)153[0781:gpdato]2.0.co；2.
［96］SHARMA P K，BHARDWAJ R，DWARAKANATH B S，et al. Metabolic oxidative stress induced by a combination of 2-DG and 6-AN enhances radiation damage selectively in malignant cells via non-coordinated expression of antioxidant enzymes［J］. Cancer Lett，2010，295（2）：154-166. DOI：10.1016/j. canlet.2010.02.021.

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