Acknowledgement
This study was supported by research grants from Zhejiang Provincial Traditional Chinese Medicine Administration (2018ZB010), Zhejiang Provincial Natural Science Foundation (LR18H160002), National Natural Science Foundation of China (32070740), Zhejiang Provincial Medical and Health Science and Technology Project (2018KY010), Zhejiang Provincial Outstanding Talent Project of Ten Thousand Talents Program, Zhejiang Provincial Qianjiang Talents Program and Zhejiang Provincial Health Innovation Talents Program to Dr. Zhang Jianbin and Zhejiang Provincial Medical and Health Science and Technology Project (2020379920) to Dr. Zhou Hongying.
References
- Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68(6):394-424. https://doi.org/10.3322/caac.21492
- van den Heerik A, Horeweg N, de Boer SM, Bosse T, Creutzberg CL. Adjuvant therapy for endometrial cancer in the era of molecular classification: radiotherapy, chemoradiation and novel targets for therapy. Int J Gynecol Cancer 2020.
- Sun X, Yan P, Zou C, Wong YK, Shu Y, Lee YM, Zhang C, Yang ND, Wang J, Zhang J. Targeting autophagy enhances the anticancer effect of artemisinin and its derivatives. Med Res Rev 2019;39(6):2172-93. https://doi.org/10.1002/med.21580
- Yao H, Liu J, Xu S, Zhu Z, Xu J. The structural modification of natural products for novel drug discovery. Expert Opin Drug Discov 2017;12(2):121-40. https://doi.org/10.1080/17460441.2016.1272757
- Hon KL, Lee VW. Challenges for drug discovery and development in China. Expert Opin Drug Discov 2017;12(1):105-13. https://doi.org/10.1080/17460441.2017.1257115
- Attele AS, Wu JA, Yuan CS. Ginseng pharmacology: multiple constituents and multiple actions. Biochem Pharmacol 1999;58(11):1685-93. https://doi.org/10.1016/S0006-2952(99)00212-9
- Christensen LP. Ginsenosides chemistry, biosynthesis, analysis, and potential health effects. Adv Food Nutr Res 2009;55:1-99. https://doi.org/10.1016/S1043-4526(08)00401-4
- Lu JM, Yao Q, Chen C. Ginseng compounds: an update on their molecular mechanisms and medical applications. Curr Vasc Pharmacol 2009;7(3):293-302. https://doi.org/10.2174/157016109788340767
- Xu T, Jin Z, Yuan Y, Wei H, Xu X, He S, Chen S, Hou W, Guo Q, Hua B. Ginsenoside Rg3 serves as an adjuvant chemotherapeutic agent and VEGF inhibitor in the treatment of non-small cell lung cancer: a meta-analysis and systematic review. Evid Based Complement Alternat Med 2016;2016:7826753.
- Lu P, Su W, Miao ZH, Niu HR, Liu J, Hua QL. Effect and mechanism of ginsenoside Rg3 on postoperative life span of patients with non-small cell lung cancer. Chin J Integr Med 2008;14(1):33-6. https://doi.org/10.1007/s11655-007-9002
- Meissner C, Lorenz H, Weihofen A, Selkoe DJ, Lemberg MK. The mitochondrial intramembrane protease PARL cleaves human Pink1 to regulate Pink1 trafficking. J Neurochem 2011;117(5):856-67. https://doi.org/10.1111/j.1471-4159.2011.07253.x
- Matsuda N, Sato S, Shiba K, Okatsu K, Saisho K, Gautier CA, Sou YS, Saiki S, Kawajiri S, Sato F, et al. PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy. J Cell Biol 2010;189(2):211-21. https://doi.org/10.1083/jcb.200910140
- Liu J, Zhang C, Hu W, Feng Z. Parkinson's disease-associated protein Parkin: an unusual player in cancer. Cancer Commun (Lond) 2018;38(1):40. https://doi.org/10.1186/s40880-018-0314-z
- Panigrahi DP, Praharaj PP, Bhol CS, Mahapatra KK, Patra S, Behera BP, Mishra SR, Bhutia SK. The emerging, multifaceted role of mitophagy in cancer and cancer therapeutics. Semin Cancer Biol 2020;66:45-58. https://doi.org/10.1016/j.semcancer.2019.07.015
- Bernardini JP, Lazarou M, Dewson G. Parkin and mitophagy in cancer. Oncogene 2017;36(10):1315-27. https://doi.org/10.1038/onc.2016.302
- Liu C, Wang J, Yang Y, Liu X, Zhu Y, Zou J, Peng S, Le TH, Chen Y, Zhao S, et al. Ginsenoside Rd ameliorates colitis by inducing p62-driven mitophagy-mediated NLRP3 inflammasome inactivation in mice. Biochem Pharmacol 2018;155:366-79. https://doi.org/10.1016/j.bcp.2018.07.010
- Xu Z, Li C, Liu Q, Yang H, Li P. Ginsenoside Rg1 protects H9c2 cells against nutritional stress-induced injury via aldolase/AMPK/PINK1 signalling. J Cell Biochem 2019;120(10):18388-97. https://doi.org/10.1002/jcb.29150
- Hou J, Yun Y, Xue J, Jeon B, Kim S. Doxorubicin-induced normal breast epithelial cellular aging and its related breast cancer growth through mitochondrial autophagy and oxidative stress mitigated by ginsenoside Rh2. Phytother Res 2020;34(7):1659-69. https://doi.org/10.1002/ptr.6636
- Bian S, Zhao Y, Li F, Lu S, Wang S, Bai X, Liu M, Zhao D, Wang J, Guo D. 20(S)-Ginsenoside Rg3 promotes HeLa cell apoptosis by regulating autophagy. Molecules 2019;24(20).
- Xia T, Wang YN, Zhou CX, Wu LM, Liu Y, Zeng QH, Zhang XL, Yao JH, Wang M, Fang JP. Ginsenoside Rh2 and Rg3 inhibit cell proliferation and induce apoptosis by increasing mitochondrial reactive oxygen species in human leukemia Jurkat cells. Mol Med Rep 2017;15(6):3591-8. https://doi.org/10.3892/mmr.2017.6459
- Yao N, Wang C, Hu N, Li Y, Liu M, Lei Y, Chen M, Chen L, Chen C, Lan P, et al. Inhibition of PINK1/Parkin-dependent mitophagy sensitizes multidrug-resistant cancer cells to B5G1, a new betulinic acid analog. Cell Death Dis 2019;10(3):232. https://doi.org/10.1038/s41419-019-1470-z
- Wu W, Tian W, Hu Z, Chen G, Huang L, Li W, Zhang X, Xue P, Zhou C, Liu L, et al. ULK1 translocates to mitochondria and phosphorylates FUNDC1 to regulate mitophagy. EMBO Rep 2014;15(5):566-75. https://doi.org/10.1002/embr.201438501
- Narendra D, Tanaka A, Suen DF, Youle RJ. Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J Cell Biol 2008;183(5):795-803. https://doi.org/10.1083/jcb.200809125
- Zhang J, Sun X, Wang L, Wong YK, Lee YM, Zhou C, Wu G, Zhao T, Yang L, Lu L, et al. Artesunate-induced mitophagy alters cellular redox status. Redox Biol 2018;19:263-73. https://doi.org/10.1016/j.redox.2018.07.025
- Veeriah S, Taylor BS, Meng S, Fang F, Yilmaz E, Vivanco I, Janakiraman M, Schultz N, Hanrahan AJ, Pao W, et al. Somatic mutations of the Parkinson's disease-associated gene PARK2 in glioblastoma and other human malignancies. Nat Genet 2010;42(1):77-82. https://doi.org/10.1038/ng.491
- Poulogiannis G, McIntyre RE, Dimitriadi M, Apps JR, Wilson CH, Ichimura K, Luo F, Cantley LC, Wyllie AH, Adams DJ, et al. PARK2 deletions occur frequently in sporadic colorectal cancer and accelerate adenoma development in Apc mutant mice. Proc Natl Acad Sci U S A 2010;107(34):15145-50. https://doi.org/10.1073/pnas.1009941107
- Tristan C, Shahani N, Sedlak TW, Sawa A. The diverse functions of GAPDH: views from different subcellular compartments. Cell Signal 2011;23(2):317-23. https://doi.org/10.1016/j.cellsig.2010.08.003
- Nicholls C, Li H, Liu JP. GAPDH: a common enzyme with uncommon functions. Clin Exp Pharmacol Physiol 2012;39(8):674-9. https://doi.org/10.1111/j.1440-1681.2011.05599.x
- Hwang S, Disatnik MH, Mochly-Rosen D. Impaired GAPDH-induced mitophagy contributes to the pathology of Huntington's disease. EMBO Mol Med 2015;7(10):1307-26. https://doi.org/10.15252/emmm.201505256
- Mandic R, Agaimy A, Pinto-Quintero D, Roth K, Teymoortash A, Schwarzbach H, Stoehr CG, Rodepeter FR, Stuck BA, Bette M. Aberrant expression of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in warthin tumors. Cancers (Basel) 2020;12(5).
- Liu J, Zhang C, Wu H, Sun XX, Li Y, Huang S, Yue X, Lu SE, Shen Z, Su X, et al. Parkin ubiquitinates phosphoglycerate dehydrogenase to suppress serine synthesis and tumor progression. J Clin Invest 2020;130(6):3253-69. https://doi.org/10.1172/jci132876
- Bertolin G, Jacoupy M, Traver S, Ferrando-Miguel R, Saint Georges T, Grenier K, Ardila-Osorio H, Muriel MP, Takahashi H, Lees AJ, et al. Parkin maintains mitochondrial levels of the protective Parkinson's disease-related enzyme 17-beta hydroxysteroid dehydrogenase type 10. Cell Death Differ 2015;22(10):1563-76. https://doi.org/10.1038/cdd.2014.224
- Gegg ME, Schapira AH. PINK1-parkin-dependent mitophagy involves ubiquitination of mitofusins 1 and 2: implications for Parkinson disease pathogenesis. Autophagy 2011;7(2):243-5. https://doi.org/10.4161/auto.7.2.14332
- Jin SM, Youle RJ. PINK1- and Parkin-mediated mitophagy at a glance. J Cell Sci 2012;125(Pt 4):795-9. https://doi.org/10.1242/jcs.093849
- Geisler S, Holmstrom KM, Skujat D, Fiesel FC, Rothfuss OC, Kahle PJ, Springer W. PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nat Cell Biol 2010;12(2):119-31. https://doi.org/10.1038/ncb2012
- Bryksin AV, Laktionov PP. Role of glyceraldehyde-3-phosphate dehydrogenase in vesicular transport from golgi apparatus to endoplasmic reticulum. Biochemistry (Mosc) 2008;73(6):619-25. https://doi.org/10.1134/S0006297908060011
- Sirover MA. Subcellular dynamics of multifunctional protein regulation: mechanisms of GAPDH intracellular translocation. J Cell Biochem 2012;113(7):2193-200. https://doi.org/10.1002/jcb.24113
- Sabharwal SS, Schumacker PT. Mitochondrial ROS in cancer: initiators, amplifiers or an Achilles' heel? Nat Rev Cancer 2014;14(11):709-21. https://doi.org/10.1038/nrc3803
- Saunders PA, Chalecka-Franaszek E, Chuang DM. Subcellular distribution of glyceraldehyde-3-phosphate dehydrogenase in cerebellar granule cells undergoing cytosine arabinoside-induced apoptosis. J Neurochem 1997;69(5):1820-8. https://doi.org/10.1046/j.1471-4159.1997.69051820.x
- Dando I, Fiorini C, Pozza ED, Padroni C, Costanzo C, Palmieri M, Donadelli M. UCP2 inhibition triggers ROS-dependent nuclear translocation of GAPDH and autophagic cell death in pancreatic adenocarcinoma cells. Biochim Biophys Acta 2013;1833(3):672-9. https://doi.org/10.1016/j.bbamcr.2012.10.028
- Colell A, Green DR, Ricci JE. Novel roles for GAPDH in cell death and carcinogenesis. Cell Death Differ 2009;16(12):1573-81. https://doi.org/10.1038/cdd.2009.137
- Ishitani R, Tanaka M, Sunaga K, Katsube N, Chuang DM. Nuclear localization of overexpressed glyceraldehyde-3-phosphate dehydrogenase in cultured cerebellar neurons undergoing apoptosis. Mol Pharmacol 1998;53(4):701-7. https://doi.org/10.1124/mol.53.4.701
- Liu CX, Xiao PG. Recent advances on ginseng research in China. J Ethnopharmacol 1992;36(1):27-38. https://doi.org/10.1016/0378-8741(92)90057-X
- Choi KT. Botanical characteristics, pharmacological effects and medicinal components of Korean Panax ginseng C A Meyer. Acta Pharmacol Sin 2008;29(9):1109-18. https://doi.org/10.1111/j.1745-7254.2008.00869.x
- Spelman K, Burns J, Nichols D, Winters N, Ottersberg S, Tenborg M. Modulation of cytokine expression by traditional medicines: a review of herbal immunomodulators. Altern Med Rev 2006;11(2):128-50.
- Song X, Hu S. Adjuvant activities of saponins from traditional Chinese medicinal herbs. Vaccine 2009;27(36):4883-90. https://doi.org/10.1016/j.vaccine.2009.06.033
- Liu J, Zhang C, Zhao Y, Yue X, Wu H, Huang S, Chen J, Tomsky K, Xie H, Khella CA, et al. Parkin targets HIF-1alpha for ubiquitination and degradation to inhibit breast tumor progression. Nat Commun 2017;8(1):1823. https://doi.org/10.1038/s41467-017-01947-w
- Tay SP, Yeo CW, Chai C, Chua PJ, Tan HM, Ang AX, Yip DL, Sung JX, Tan PH, Bay BH, et al. Parkin enhances the expression of cyclin-dependent kinase 6 and negatively regulates the proliferation of breast cancer cells. J Biol Chem 2010;285(38):29231-8. https://doi.org/10.1074/jbc.M110.108241
- Saha T. LAMP2A overexpression in breast tumors promotes cancer cell survival via chaperone-mediated autophagy. Autophagy 2012;8(11):1643-56. https://doi.org/10.4161/auto.21654
- Kulikov AV, Luchkina EA, Gogvadze V, Zhivotovsky B. Mitophagy: link to cancer development and therapy. Biochem Biophys Res Commun 2017;482(3):432-9. https://doi.org/10.1016/j.bbrc.2016.10.088
- Chourasia AH, Boland ML, Macleod KF. Mitophagy and cancer. Cancer Metab 2015;3:4. https://doi.org/10.1186/s40170-015-0130-8
- Schumacker PT. Reactive oxygen species in cancer: a dance with the devil. Cancer Cell 2015;27(2):156-7. https://doi.org/10.1016/j.ccell.2015.01.007
- Sun HY, Lee JH, Han YS, Yoon YM, Yun CW, Kim JH, Song YS, Lee SH. Pivotal roles of ginsenoside Rg3 in tumor apoptosis through regulation of reactive oxygen species. Anticancer Res 2016;36(9):4647-54. https://doi.org/10.21873/anticanres.11015
- Ahmmed B, Kampo S, Khan M, Faqeer A, Kumar SP, Yulin L, Liu JW, Yan Q. Rg3 inhibits gemcitabine-induced lung cancer cell invasiveness through ROS-dependent, NF-kappaB- and HIF-1alpha-mediated downregulation of PTX3. J Cell Physiol 2019;234(7):10680-97. https://doi.org/10.1002/jcp.27731
- Peng Y, Zhang R, Yang X, Zhang Z, Kang N, Bao L, Shen Y, Yan H, Zheng F. Ginsenoside Rg3 suppresses the proliferation of prostate cancer cell line PC3 through ROS-induced cell cycle arrest. Oncol Lett 2019;17(1):1139-45.