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Zhaoshi BAI


Lingman MA


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Journal of Zhejiang University SCIENCE B 2022 Vol.23 No.2 P.89-101


Autophagy and cancer treatment: four functional forms of autophagy and their therapeutic applications

Author(s):  Zhaoshi BAI, Yaling PENG, Xinyue YE, Zhixian LIU, Yupeng LI, Lingman MA

Affiliation(s):  Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & the Affiliated Cancer Hospital of Nanjing Medical University, Nanjing 210009, China; more

Corresponding email(s):   zhaoshi_bai@njmu.edu.cn, lingman_ma@cpu.edu.cn

Key Words:  Autophagy, Cancer treatment, Precision treatment, Cell death mode

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Zhaoshi BAI, Yaling PENG, Xinyue YE, Zhixian LIU, Yupeng LI, Lingman MA. Autophagy and cancer treatment: four functional forms of autophagy and their therapeutic applications[J]. Journal of Zhejiang University Science B, 2022, 23(2): 89-101.

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author="Zhaoshi BAI, Yaling PENG, Xinyue YE, Zhixian LIU, Yupeng LI, Lingman MA",
journal="Journal of Zhejiang University Science B",
publisher="Zhejiang University Press & Springer",

%0 Journal Article
%T Autophagy and cancer treatment: four functional forms of autophagy and their therapeutic applications
%A Zhaoshi BAI
%A Yaling PENG
%A Xinyue YE
%A Zhixian LIU
%A Yupeng LI
%A Lingman MA
%J Journal of Zhejiang University SCIENCE B
%V 23
%N 2
%P 89-101
%@ 1673-1581
%D 2022
%I Zhejiang University Press & Springer
%DOI 10.1631/jzus.B2100804

T1 - Autophagy and cancer treatment: four functional forms of autophagy and their therapeutic applications
A1 - Zhaoshi BAI
A1 - Yaling PENG
A1 - Xinyue YE
A1 - Zhixian LIU
A1 - Yupeng LI
A1 - Lingman MA
J0 - Journal of Zhejiang University Science B
VL - 23
IS - 2
SP - 89
EP - 101
%@ 1673-1581
Y1 - 2022
PB - Zhejiang University Press & Springer
ER -
DOI - 10.1631/jzus.B2100804

Cancer is the leading cause of death worldwide. Drugs play a pivotal role in cancer treatment, but the complex biological processes of cancer cells seriously limit the efficacy of various anticancer drugs. autophagy, a self-degradative system that maintains cellular homeostasis, universally operates under normal and stress conditions in cancer cells. The roles of autophagy in cancer treatment are still controversial because both stimulation and inhibition of autophagy have been reported to enhance the effects of anticancer drugs. Thus, the important question arises as to whether we should try to strengthen or suppress autophagy during cancer therapy. Currently, autophagy can be divided into four main forms according to its different functions during cancer treatment: cytoprotective (cell survival), cytotoxic (cell death), cytostatic (growth arrest), and nonprotective (no contribution to cell death or survival). In addition, various cell death modes, such as apoptosis, necrosis, ferroptosis, senescence, and mitotic catastrophe, all contribute to the anticancer effects of drugs. The interaction between autophagy and these cell death modes is complex and can lead to anticancer drugs having different or even completely opposite effects on treatment. Therefore, it is important to understand the underlying contexts in which autophagy inhibition or activation will be beneficial or detrimental. That is, appropriate therapeutic strategies should be adopted in light of the different functions of autophagy. This review provides an overview of recent insights into the evolving relationship between autophagy and cancer treatment.




Darkslateblue:Affiliate; Royal Blue:Author; Turquoise:Article


[1]AkalayI, JanjiB, HasmimM, et al., 2013. EMT impairs breast carcinoma cell susceptibility to CTL-mediated lysis through autophagy induction. Autophagy, 9(7):1104-1106.

[2]AryaBD, MittalS, JoshiP, et al., 2018. Graphene oxide-chloroquine nanoconjugate induce necroptotic death in A549 cancer cells through autophagy modulation. Nanomedicine, 13(18):2261-2282.

[3]BaiZS, GaoMQ, ZhangHJ, et al., 2017. BZML, a novel colchicine binding site inhibitor, overcomes multidrug resistance in A549/Taxol cells by inhibiting P-gp function and inducing mitotic catastrophe. Cancer Lett, 402:81-92.

[4]BaiZS, GaoMQ, XuXB, et al., 2018. Overcoming resistance to mitochondrial apoptosis by BZML-induced mitotic catastrophe is enhanced by inhibition of autophagy in A549/Taxol cells. Cell Prolif, 51(4):e12450.

[5]BaiZS, LiuXL, GuanQ, et al., 2020. 5-(3,4,5-trimethoxybenzoyl)-4-methyl-2-‍(p-tolyl) imidazol (BZML) targets tubulin and DNA to induce anticancer activity and overcome multidrug resistance in colorectal cancer cells. Chem Biol Interact, 315:108886.

[6]Ben-AmarA, MlikiA, 2021. Timely gene detection assay and reliable screening of genetically engineered plants using an improved direct PCR-based technology. Transgenic Res, 30(3):263-274.

[7]BialikS, DasariSK, KimchiA, 2018. Autophagy-dependent cell death—where, how and why a cell eats itself to death. J Cell Sci, 131(18):jcs215152.

[8]CallJA, NichenkoAS, 2020. Autophagy: an essential but limited cellular process for timely skeletal muscle recovery from injury. Autophagy, 16(7):1344-1347.

[9]JMNLCardozo, SchmidtMK, van’t VeerLJ, et al., 2021. Combining method of detection and 70-gene signature for enhanced prognostication of breast cancer. Breast Cancer Res Treat, 189(2):399-410.

[10]Chaeichi-TehraniN, FernsGA, HassanianSM, et al., 2021. The therapeutic potential of targeting autophagy in the treatment of cancer. Curr Cancer Drug Targets, 21(9):725-736.

[11]ChangCH, BijianK, WernicD, et al., 2019. A novel orally available seleno-purine molecule suppresses triple-negative breast cancer cell proliferation and progression to meta

[12]stasis by inducing cytostatic autophagy. Autophagy, 15(8):1376-1390.

[13]ChangCM, ShiXS, JensenLE, et al., 2021. Reconstitution of cargo-induced LC3 lipidation in mammalian selective autophagy. Sci Adv, 7(17):eabg4922.

[14]ChenGQ, BenthaniFA, WuJ, et al., 2020. Artemisinin compounds sensitize cancer cells to ferroptosis by regulating iron homeostasis. Cell Death Differ, 27(1):242-254.

[15]ChenJH, ZhangLM, ZhouH, et al., 2018. Inhibition of autophagy promotes cisplatin-induced apoptotic cell death through Atg5 and Beclin 1 in A549 human lung cancer cells. Mol Med Rep, 17(5):6859-6865.

[16]DixonSJ, LembergKM, LamprechtMR, et al., 2012. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell, 149(5):1060-1072.

[17]DouQH, ChenHN, WangK, et al., 2016. Ivermectin induces cytostatic autophagy by blocking the PAK1/Akt axis in breast cancer. Cancer Res, 76(15):4457-4469.

[18]EndoS, HoshiM, MatsunagaT, et al., 2018. Autophagy inhibition enhances anticancer efficacy of artepillin C, a cinnamic acid derivative in Brazilian green propolis. Biochem Biophys Res Commun, 497(1):437-443.

[19]Feliz-MosqueaYR, ChristensenAA, WilsonAS, et al., 2018. Combination of anthracyclines and anti-CD47 therapy inhibit invasive breast cancer growth while preventing cardiac toxicity by regulation of autophagy. Breast Cancer Res Treat, 172(1):69-82.

[20]GalluzziL, GreenDR, 2019. Autophagy-independent functions of the autophagy machinery. Cell, 177(7):1682-1699.

[21]GalluzziL, VitaleI, AaronsonSA, et al., 2018. Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. Cell Death Differ, 25(3):486-541.

[22]GaoMH, MonianP, PanQH, et al., 2016. Ferroptosis is an autophagic cell death process. Cell Res, 26(9):1021-1032.

[23]GengSC, LiXL, FangWH, 2020. Porcine circovirus 3 capsid protein induces autophagy in HEK293T cells by inhibiting phosphorylation of the mammalian target of rapamycin. J Zhejiang Univ-Sci B (Biomed & Biotechnol), 21(7):560-570.

[24]GewirtzDA, 2014. The four faces of autophagy: implications for cancer therapy. Cancer Res, 74(3):647-651.

[25]GiatromanolakiA, KoukourakisMI, GeorgiouI, et al., 2018. LC3A, LC3B and Beclin-1 expression in gastric cancer. Anticancer Res, 38(12):6827-6833.

[26]HaasNB, ApplemanLJ, SteinM, et al., 2019. Autophagy inhibition to augment mTOR inhibition: a phase I/II trial of everolimus and hydroxychloroquine in patients with previously treated renal cell carcinoma. Clin Cancer Res, 25(7):2080-2087.

[27]HansenAR, TannockIF, TempletonA, et al., 2019. Pantoprazole affecting docetaxel resistance pathways via autophagy (PANDORA): phase II trial of high dose pantoprazole (autophagy inhibitor) with docetaxel in metastatic castration-resistant prostate cancer (mCRPC). Oncologist, 24(9):1188-1194.

[28]HouW, XieYC, SongXX, et al., 2016. Autophagy promotes ferroptosis by degradation of ferritin. Autophagy, 12(8):1425-1428.

[29]HuYL, JahangiriA, DeLayM, et al., 2012. Tumor cell autophagy as an adaptive response mediating resistance to treatments such as antiangiogenic therapy. Cancer Res, 72(17):4294-4299.

[30]HuangYH, YangPM, ChuahQY, et al., 2014. Autophagy promotes radiation-induced senescence but inhibits bystander effects in human breast cancer cells. Autophagy, 10(7):1212-1228.

[31]JeongS, KimBG, KimDY, et al., 2019. Cannabidiol overcomes oxaliplatin resistance by enhancing NOS3- and SOD2-induced autophagy in human colorectal cancer cells. Cancers, 11(6):781.

[32]KimSY, HwangboH, KimMY, et al., 2021. Coptisine induces autophagic cell death through down-regulation of PI3K/Akt/mTOR signaling pathway and up-regulation of ROS-mediated mitochondrial dysfunction in hepatocellular carcinoma Hep3B cells. Arch Biochem Biophys, 697:108688.

[33]KongYL, HuangY, WuJZ, et al., 2018. Expression of autophagy related genes in chronic lymphocytic leukemia is associated with disease course. Leuk Res, 66:8-14.

[34]LawBYK, MichelangeliF, QuYQ, et al., 2019. Neferine induces autophagy-dependent cell death in apoptosis-resistant cancers via ryanodine receptor and Ca2+-dependent mechanism. Sci Rep, 9:20034.

[35]LevyJMM, TowersCG, ThorburnA, 2017. Targeting autophagy in cancer. Nat Rev Cancer, 17(9):528-542.

[36]LiL, WangYB, JiaoL, et al., 2019. Protective autophagy decreases osimertinib cytotoxicity through regulation of stem cell-like properties in lung cancer. Cancer Lett, 452:191-202.

[37]LinJF, LinYC, TsaiTF, et al., 2017. Cisplatin induces protective autophagy through activation of BECN1 in human bladder cancer cells. Drug Des Devel Ther, 11:1517-1533.

[38]LinSY, HsiehSY, FanYT, et al., 2018. Necroptosis promotes autophagy-dependent upregulation of DAMP and results in immunosurveillance. Autophagy, 14(5):778-795.

[39]LinTY, ChanHH, ChenSH, et al., 2020. BIRC5/survivin is a novel ATG12-ATG5 conjugate interactor and an autophagy-induced DNA damage suppressor in human cancer and mouse embryonic fibroblast cells. Autophagy, 16(7):1296-1313.

[40]LiuYM, YangSS, WangKL, et al., 2020. Cellular senescence and cancer: focusing on traditional Chinese medicine and natural products. Cell Prolif, 53(10):e12894.

[41]LiuYY, WangN, ZhangSK, et al., 2018. Autophagy protects bone marrow mesenchymal stem cells from palmitate-induced apoptosis through the ROS-JNK/p38 MAPK signaling pathways. Mol Med Rep, 18(2):1485-1494.

[42]LuZM, RenYD, YangL, et al., 2021. Inhibiting autophagy enhances sulforaphane-induced apoptosis via targeting NRF2 in esophageal squamous cell carcinoma. Acta Pharm Sin B, 11(5):1246-1260.

[43]LystadAH, CarlssonSR, SimonsenA, 2019. Toward the function of mammalian ATG12-ATG5-ATG16L1 complex in autophagy and related processes. Autophagy, 15(8):1485-1486.

[44]MaRY, YuDD, PengY, et al., 2021. Resveratrol induces AMPK and mTOR signaling inhibition-mediated autophagy and apoptosis in multiple myeloma cells. Acta Biochim Biophys Sin, 53(6):775-783.

[45]MaSM, DielschneiderRF, HensonES, et al., 2017. Ferroptosis and autophagy induced cell death occur independently after siramesine and lapatinib treatment in breast cancer cells. PLoS ONE, 12(8):e0182921.

[46]MalhotraJ, JabbourS, OrlickM, et al., 2019. Phase Ib/II study of hydroxychloroquine in combination with chemotherapy in patients with metastatic non-small cell lung cancer (NSCLC). Cancer Treat Res Commun, 21:100158.

[47]MaskeyD, YousefiS, SchmidI, et al., 2013. ATG5 is induced by DNA-damaging agents and promotes mitotic catastrophe independent of autophagy. Nat Commun, 4:2130.

[48]McKayLK, WhiteJP, 2021. The AMPK/p27Kip1 pathway as a novel target to promote autophagy and resilience in aged cells. Cells, 10(6):1430.

[49]MiricescuD, BalanDG, TulinA, et al., 2021. PI3K/AKT/mTOR signalling pathway involvement in renal cell carcinoma pathogenesis (Review). Exp Ther Med, 21(5):540.

[50]MoHJ, RennaCE, MooreHCF, et al., 2021. Real-world outcomes of everolimus and exemestane for the treatment of metastatic hormone receptor-positive breast cancer in patients previously treated with CDK4/6 inhibitors. Clin Breast Cancer, in press.

[51]NajafovA, ChenHB, YuanJJ, 2017. Necroptosis and cancer. Trends Cancer, 3(4):294-301.

[52]NamHY, HanMW, ChangHW, et al., 2013. Prolonged autophagy by MTOR inhibitor leads radioresistant cancer cells into senescence. Autophagy, 9(10):1631-1632.

[53]PatelNH, XuJW, SalehT, et al., 2020. Influence of nonprotective autophagy and the autophagic switch on sensitivity to cisplatin in non-small cell lung cancer cells. Biochem Pharmacol, 175:113896.

[54]ShangJ, ChenWM, LiuS, et al., 2019. CircPAN3 contributes to drug resistance in acute myeloid leukemia through regulation of autophagy. Leuk Res, 85:106198.

[55]SharmaK, GoeheRW, DiX, et al., 2014. A novel cytostatic form of autophagy in sensitization of non-small cell lung cancer cells to radiation by vitamin D and the vitamin D analog, EB 1089. Autophagy, 10(12):2346-2361.

[56]SorokinaIV, DenisenkoTV, ImrehG, et al., 2017. Involvement of autophagy in the outcome of mitotic catastrophe. Sci Rep, 7:14571.

[57]SunBY, LiuYQ, HeDH, et al., 2021. Traditional Chinese medicines and their active ingredients sensitize cancer cells to trail-induced apoptosis. J Zhejiang Univ-Sci B (Biomed & Biotechnol), 22(3):190-203.

[58]SungHH, GiMY, ChaJA, et al., 2021. Gender difference in the relationship between lipid accumulation product index and pulse pressure in nondiabetic Korean adults: The Korean National Health and Nutrition Examination Survey 2013‒2014. Clin Exp Hypertens, in press.

[59]ThorburnA, 2020. A new mechanism for autophagy regulation of anti-tumor immune responses. Autophagy, 16(12):2282-2284.

[60]ToozeSA, DikicI, 2016. Autophagy captures the Nobel Prize. Cell, 167(6):1433-1435.

[61]ToriiS, ShintokuR, KubotaC, et al., 2016. An essential role for functional lysosomes in ferroptosis of cancer cells. Biochem J, 473(6):769-777.

[62]TowersCG, WodetzkiD, ThorburnA, 2020. Autophagy and cancer: modulation of cell death pathways and cancer cell adaptations. J Cell Biol, 219(1):e201909033.

[63]Tyutyunyk-MasseyL, GewirtzDA, 2020. Roles of autophagy in breast cancer treatment: target, bystander or benefactor. Semin Cancer Biol, 66:155-162.

[64]ValenzuelaCA, VargasL, MartinezV, et al., 2017. Palbociclib-induced autophagy and senescence in gastric cancer cells. Exp Cell Res, 360(2):390-396.

[65]van der VeldenDL, HoesLR, van der WijngaartH, et al., 2019. The drug rediscovery protocol facilitates the expanded use of existing anticancer drugs. Nature, 574(7776):127-131.

[66]VidalL, VictoriaI, GabaL, et al., 2021. A first-in-human phase I/Ib dose-escalation clinical trial of the autophagy inducer ABTL0812 in patients with advanced solid tumours. Eur J Cancer, 146:87-94.

[67]VujićN, BradićI, GoeritzerM, et al., 2021. ATG7 is dispensable for LC3-PE conjugation in thioglycolate-elicited mouse peritoneal macrophages. Autophagy, 17(11):3402-3407.

[68]WangK, GaoW, DouQH, et al., 2016. Ivermectin induces PAK1-mediated cytostatic autophagy in breast cancer. Autophagy, 12(12):2498-2499.

[69]WangQW, LiuWX, LiuGP, et al., 2021. AMPK-mTOR-ULK1-mediated autophagy protects carbon tetrachloride-induced acute hepatic failure by inhibiting p21 in rats. J Toxicol Pathol, 34(1):73-82.

[70]WangXY, LiHQ, LiW, et al., 2020. The role of Caspase-1/GSDMD-mediated pyroptosis in Taxol-induced cell death and a Taxol-resistant phenotype in nasopharyngeal carcinoma regulated by autophagy. Cell Biol Toxicol, 36(5):437-457.

[71]WangYP, GaoWQ, ShiXY, et al., 2017. Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin. Nature, 547(7661):99-103.

[72]WenN, LvQ, DuZG, 2020. MicroRNAs involved in drug resistance of breast cancer by regulating autophagy. J Zhejiang Univ-Sci B (Biomed & Biotechnol), 21(9):690-702.

[73]WuSH, SunCB, LiYY, et al., 2015. Autophagy-related genes Raptor, Rictor, and Beclin1 expression and relationship with multidrug resistance in colorectal carcinoma. Hum Pathol, 46(11):1752-1759.

[74]XiGM, HuXY, WuBL, et al., 2011. Autophagy inhibition promotes paclitaxel-induced apoptosis in cancer cells. Cancer Lett, 307(2):141-148.

[75]Xu HD, Qin ZH, 2019. Beclin 1, Bcl-2 and autophagy.‍In: Qin ZH (Ed.), Autophagy: Biology and Diseases. Adva‍nces in Experimental Medicine and Biology, Vol. 1206. Springer, Singapore, p.109-126.

[76]XuJ, JiangJK, LiXL, et al., 2020. Comparative transcriptomic analysis of vascular endothelial cells after hypoxia/re-oxygenation induction based on microarray technology. J Zhejiang Univ-Sci B (Biomed & Biotechnol), 21(4):291-304.

[77]XuJW, PatelNH, SalehT, et al., 2018. Differential radiation sensitivity in p53 wild-type and p53-deficient tumor cells associated with senescence but not apoptosis or (nonprotective) autophagy. Radiat Res, 190(5):538-557.

[78]YamamotoK, VenidaA, YanoJ, et al., 2020. Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I. Nature, 581(7806):100-105.

[79]YangM, YangXM, YinDH, et al., 2018. Beclin1 enhances cisplatin-induced apoptosis via Bcl-2-modulated autophagy in laryngeal carcinoma cells Hep-2. Neoplasma, 65(1):42-48.

[80]YuP, WangHY, TianM, et al., 2019. Eukaryotic elongation factor-2 kinase regulates the cross-talk between autophagy and pyroptosis in doxorubicin-treated human melanoma cells in vitro. Acta Pharmacol Sin, 40(9):1237-1244.

[81]ZehHJ, BaharyN, BooneBA, et al., 2020. A randomized phase II preoperative study of autophagy inhibition with high-dose hydroxychloroquine and gemcitabine/nab-paclitaxel in pancreatic cancer patients. Clin Cancer Res, 26(13):3126-3134.

[82]ZhangJC, YinHL, ChenQD, et al., 2021. Basophils as a potential therapeutic target in cancer. J Zhejiang Univ-Sci B (Biomed & Biotechnol), 22(12):971-984.

[83]ZhangQ, WangXB, CaoSJ, et al., 2020. Berberine represses human gastric cancer cell growth in vitro and in vivo by inducing cytostatic autophagy via inhibition of MAPK/mTOR/p70S6K and Akt signaling pathways. Biomed Pharmacother, 128:110245.

[84]ZhangRJ, ChenJ, MaoLZ, et al., 2020. Nobiletin triggers reactive oxygen species-mediated pyroptosis through regulating autophagy in ovarian cancer cells. J Agric Food Chem, 68(5):1326-1336.

[85]ZhangY, HuangWH, ZhengZM, et al., 2021. Cigarette smoke-inactivated SIRT1 promotes autophagy-dependent senescence of alveolar epithelial type 2 cells to induce pulmonary fibrosis. Free Radic Biol Med, 166:116-127.

[86]ZhaoMM, WangRS, ZhouYL, et al., 2020. Emerging relationship between RNA helicases and autophagy. J Zhejiang Univ-Sci B (Biomed & Biotechnol), 21(10):767-778.

[87]ZhengHC, ZhaoS, XueH, et al., 2020. The roles of Beclin 1 expression in gastric cancer: a marker for carcinogenesis, aggressive behaviors and favorable prognosis, and a target of gene therapy. Front Oncol, 10:613679.

[88]ZhouBY, YangCH, YanX, et al., 2021. LETM1 knockdown promotes autophagy and apoptosis through AMP-activated protein kinase phosphorylation-mediated Beclin-1/Bcl-2 complex dissociation in hepatocellular carcinoma. Front Oncol, 10:606790.

[89]ZhouXJ, ChenY, WangFF, et al., 2020. Artesunate induces autophagy dependent apoptosis through upregulating ROS and activating AMPK-mTOR-ULK1 axis in human bladder cancer cells. Chem Biol Interact, 331:109273.

[90]ZhuangCL, ChenFE, 2020. Small-molecule inhibitors of necroptosis: current status and perspectives. J Med Chem, 63(4):1490-1510.

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