Molecular Mechanisms Underlying Autophagy-Mediated Treatment Resistance in Cancer
Abstract
:1. Introduction
2. Autophagy Contributes to Treatment Resistance in Cancer
2.1. Autophagy and Resistance Against Chemotherapy
Name | Mechanism of Action | Targeted Stage in Autophagy | Ref. |
---|---|---|---|
Inhibitors that target late stages of autophagy | |||
Lys05 | Lysosomotropic agent |
| [46,47] |
Chloroquine (CQ) | Lysosomotropic agent |
| [48,49] |
Hydroxychloroquine (HCQ) | |||
Quinacrine (QNX) | |||
IITZ-01 | Lysosomotropic agent |
| [50] |
ROC-325 | unknown |
| [51,52,53] |
Bafilomycin A1 (Baf A1) | Vacuolar ATPase inhibitor |
| [54] |
ECDD-S27 | Vacuolar ATPase inhibitor |
| [55] |
Ca-5f | Unknown |
| [56] |
EACC | Syntaxin 17 (STX17) translocation inhibitor |
| [57] |
MHY1485 | Mammalian target of rapamycin (mTOR) activator |
| [58] |
Pepstatin A | Acid protease inhibitor |
| [59,60] |
E64-d | Acid protease inhibitor |
| [59,60] |
Alpha-hederin | Unknown |
| [61] |
Inhibitors that target early stages of autophagy | |||
SB02024 | Vacuolar protein sorting protein 34 (Vps34) inhibitor |
| [62] |
SAR405 | Vacuolar protein sorting protein 18 and 34 (Vps18 and Vps34) inhibitor |
| [63] |
PIK-III | Vacuolar protein sorting protein 34 (Vps34) inhibitor |
| [64] |
Autophinib | Vacuolar protein sorting protein 34 (Vps34) inhibitor |
| [65] |
SBI-0206965 | Unc-51-like kinase 1 (ULK1) inhibitor |
| [66] |
ULK-100, ULK-101 | Unc-51-like kinase 1 (ULK1) inhibitor |
| [67] |
LY294002 | Phosphoinositide 3-kinase (PI3) inhibitor |
| [68,69] |
3-Methyladenine (3-MA) | Phosphoinositide 3-kinase (PI3) inhibitor |
| [70] |
Wortmannin | Phosphoinositide 3-kinase (PI3) inhibitor |
| [68,71,72] |
Spautin-1 | Ubiquitin Specific Peptidase 10 and 13 (USP10 and USP13) inhibitor |
| [73,74] |
NSC185058 | Autophagy-related (ATG) protein 4A and 4B (ATG4A and ATG4B) inhibitor |
| [75] |
UAMC-2526 | Autophagy-related (ATG) protein 4B (ATG4B) inhibitor |
| [76] |
DMP-1 | unknown |
| [77] |
Inhibitors that target both early and late stages of autophagy | |||
Tioconazole | Autophagy-related (ATG) protein 4A and 4B (ATG4A and ATG4B) inhibitor |
| [78] |
LV-320 | Autophagy-related (ATG) protein 4A and 4B (ATG4A and ATG4B) inhibitor |
| [79] |
S130 | Autophagy-related (ATG) protein 4A and 4B (ATG4A and ATG4B) inhibitor |
| [80] |
Xanthium strumarium Fruit Extract | Autophagy-related (ATG) protein 4B (ATG4B) inhibitor |
| [81] |
Verteporfin | unknown |
| [82] |
Cancer Type | Chemotherapeutic Agent | Mode of Autophagy Inhibition | Ref. | |
---|---|---|---|---|
Pharmacological | Genetic | |||
Bladder cancers | Cisplatin, Gemcitabine, Mitomycin, Pirarubicin | CQ, HCQ, Baf A1, Wortmannin, 3-MA | ATG7 shRNA, ATG12 shRNA, BECN1 shRNA, BECN1 siRNA, ATG3 siRNA | [83,84,85,86,87] |
Bone cancers | Doxorubicin, Cisplatin, Methotrexate, Paclitaxel | Spautin-1, 3-MA, CQ | BECN1 shRNA, BECN1-targeting deoxyribozyme, miR-410 (ATG16L knockdown), ATG14 siRNA, ATG7 siRNA | [88,89,90,91,92,93,94,95,96,97,98] |
Breast cancers | 5-Fluorouracil, Doxorubicin, Docetaxel, Adriamycin, Cyclophosphamide, Epirubicin, Paclitaxel, Cisplatin, Gemcitabine | Baf A1, CQ, HCQ, 3-MA, Verteporfin | ATG5 shRNA, ATG5 siRNA, ATG7 siRNA, FIP200 shRNA, ATG13 shRNA, BECN1 shRNA, BECN1 siRNA, BECN1 CRISPR/Cas9 KO, BNIP3L CRISPR/Cas9 KO, AMBRA1 shRNA | [99,100,101,102,103,104,105,106,107] |
Cervical cancers | Cisplatin, Oncothermia, Paclitaxel | 3-MA, CQ, Baf A1 | BECN1 siRNA, ATG5 siRNA, ATG7 siRNA | [108,109,110,111,112] |
Colorectal cancers | 5-FU, Oxaliplatin | CQ, 3-MA, Baf A1 | ATG7 siRNA, BECN1 siRNA, ATG5 siRNA | [113,114,115,116] |
Endometrial cancers | Paclitaxel, Cisplatin, Resveratrol, Oncothermia | CQ, 3-MA | BECN1 shRNA, ATG5 siRNA, ATG7 siRNA | [117,118,119,120,121] |
Gastric cancers | Vincristine, 5-fluorouracil, Cisplatin, Bufalin, Matrine, Oxaliplatin, Cinobufagin | CQ, 3-MA, Baf A1 | miR-23b (ATG12 knockdown), ATG5 siRNA | [122,123,124,125,126,127,128,129,130,131,132] |
Gliomas | Temozolomide, Vorinostat | HCQ, CQ, 3-MA, QNX, Baf A1, ATG4B inhibitor (NSC185058) | LC3A siRNA, LC3B siRNA, TFEB siRNA, ATG4C shRNA, ATG4B shRNA | [133,134,135,136,137,138,139,140] |
Head and neck cancers | Paclitaxel, Cisplatin, Nedaplatin | 3-MA, CQ, Baf A1 | LC3B siRNA, ATG3 siRNA, ATG5 siRNA, ATG6 siRNA, ATG7 siRNA | [141,142,143,144,145,146] |
Liver cancers | Epirubicin, Oxaliplatin, Mitomycin, Cisplatin, Doxorubicin | 3-MA, CQ, Baf A1 | ATG4B shRNA, ATG5 siRNA, ATG5 shRNA, ATG7 shRNA, LC3 shRNA, miR-101 (RAB5A, STMN1, ATG4B knockdown) | [147,148,149,150,151,152,153,154,155] |
Lung cancers | Paclitaxel, Camptothecin, Cisplatin, 5-fluorouracil, Gemcitabine, Pterostilbene | 3-MA, CQ, Alpha-hederin, Baf A1, ATG4B inhibitors (Compound 1, 17) | ATG7 siRNA, BECN1 siRNA, ATG5 siRNA | [61,141,156,157,158,159,160,161,162,163] |
Neuroblastomas | Vincristine, Doxorubicin, Cisplatin, Paclitaxel | HCQ, 3-MA | ATG5 shRNA, ATG5 siRNA, BECN1 siRNA, TRP14 siRNA | [164,165,166] |
Ovarian cancers | Cisplatin, Carboplatin, Vincristine, Gemcitabine, Ifosfamide, Docetaxel, Paclitaxel | 3-MA, CQ, Quinacrine | ATG5 siRNA, BECN1 siRNA, AMBRA1 shRNA, ATG5 CRISPR/Cas9 KO, miR-204 (LC3B and ATG7 knockdown) | [167,168,169,170,171,172,173,174,175,176] |
Pancreatic cancers | Doxorubicin, Gemcitabine, Docetaxel | CQ, Verteporfin | ATG7 siRNA, ATG12 siRNA, USP22 siRNA, miR-23b (ATG12 knockdown), miR-29a (ATG9A and TFEB knockdown), miR-29c (USP22 knockdown), miR-137 (ATG5 knockdown) | [177,178,179,180,181,182,183,184,185] |
Skin cancers | Temozolomide, Cisplatin | CQ, HCQ, LY294002 | ATG5 shRNA | [186,187,188] |
2.2. Autophagy and Resistance Against Targeted Agents
2.3. Clinical Trials
3. Crosstalk between Autophagy and Diverse Signaling Pathways Contributes to Treatment Resistance in Cancer
3.1. The Contributions of Autophagy and Major Signaling Pathways to Pro-Survival Responses that Resist Anti-Cancer Therapies—Guilt by Association?
3.1.1. Mitogen-Activated Protein Kinase (MAPK) Signaling
The Role of MAPK Signaling in Cancer Progression
MAPK Signaling and Autophagy: Connections to Treatment Resistance in Cancers
3.1.2. Protein Kinase B/AKT (PKB/AKT) Pathway
The Role of PKB/AKT Signaling in Cancer Progression
AKT Signaling and Autophagy: Connections to Treatment Resistance in Cancers
3.2. The Cellular Recycling and Self-Degradative Functions of Autophagy Contribute to Chemoresistance in Cancers
3.2.1. The p62-KEAP1-NRF2 Axis
p62-KEAP1-NRF2 Signaling in Cancers
Crosstalk between Autophagy Pathway and the p62-KEAP1-NRF2 Axis in Cancer Progression and Chemoresistance
3.2.2. The FOXO3A-PUMA Axis
FOXO3A-PUMA Signaling in Cancer
Crosstalk between Autophagy Pathway and the FOXO3A-PUMA Axis in Cancer Progression and Chemoresistance
4. Conclusions and Perspectives
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Targeted Agent | Cancer Types | Mode of Autophagy Inhibition | Ref. | |
---|---|---|---|---|
Pharmacological | Genetic | |||
Monoclonal antibodies | ||||
Bevacizumab (VEGF (vascular endothelial growth factor) inhibitor) | Gliomas, Colorectal cancers, Liver cancers | CQ, HCQ | BECN1 siRNA (small interfering Ribonucleic Acid), ATG7 shRNA (short hairpin Ribonucleic Acid) | [113,192,193,194,195,196] |
Trastuzumab (HER2 (human epidermal growth factor receptor 2) inhibitor) | Breast cancers | 3-MA, Baf A1 | LC3B siRNA, ATG4B siRNA, ATG12 shRNA, ATG4B siRNA | [197,198,199,200] |
Cetuximab (EGFR (epidermal growth factor receptor) inhibitor) | Vulvar cancers, Lung cancers, Head and neck cancers | CQ, 3-MA | BECN1 siRNA, ATG7 siRNA | [201,202,203] |
Small molecule inhibitors | ||||
Sorafenib (multi-kinase inhibitor—VEGFRs, PDGFRs (platelet-derived growth factor receptor), RAF (Rapidly Accelerated Fibrosarcoma) kinases) | Endometrial cancers, Liver cancers, Kidney cancers, Gliomas, Desmoid tumors | CQ, 3-MA, Baf A1 | BECN1 siRNA, BECN1 shRNA, ATG5 siRNA, ATG5 shRNA, miR (microRNA)-375 (ATG7 knockdown) | [204,205,206,207,208,209,210] |
Linifanib (multi-kinase inhibitor—VEGFRs and PDFRs) | Liver cancers | CQ, 3-MA | ATG7 siRNA, ATG5 siRNA | [211] |
Sunitinib (Multi-kinase inhibitor—PDGFRs, VEGFRs, KIRs (Killer cell immunoglobulin like receptors), FLT-3 (fms like tyrosine kinase-3), CSF-1R (Colony stimulating factor 1 receptor), RET (rearranged during transfection) kinases) | Ovarian cancers, Kidney cancers, Prostate cancers, Pancreatic cancers | Lys05, CQ, 3-MA, Baf A1 | ATG7 siRNA, ATG5 siRNA, ATG5 shRNA, LAMP2 shRNA | [212,213,214,215,216] |
Gefitinib (EGFR inhibitor) | Breast cancers, Bladder cancers, Skin cancers, Lung cancers, Liver cancers, Pancreatic cancers | 3-MA, Baf A1, CQ, HCQ | ATG12 siRNA, BECN1 siRNA, ATG7 siRNA, ATG5 siRNA, VPS34 siRNA, miR-153-3p (ATG5 knockdown) | [217,218,219,220,221,222,223,224,225,226,227,228] |
Osimertinib (EGFR inhibitor) | Lung cancers, Breast cancers, Colorectal cancers | Spautin-1, CQ, 3-MA | BECN1 siRNA, ATG5 siRNA | [229,230,231,232,233] |
Erlotinib (EGFR inhibitor) | Lung cancers, Glioblastomas, Head and neck cancers | l CQ, 3-MA, Quinacrine | ATG5 siRNA, ATG7 siRNA, BECN1 siRNA, LC3 siRNA | [228,234,235,236,237,238,239] |
Everolimus (mTORC1 (mammalian target of rapamycin complex 1) inhibitor) | Blood cancers, Kidney cancers, Bladder cancers, Breast cancer, Neuroendocrine tumors | HCQ, CQ, Baf A1, 3-MA | - | [240,241,242,243,244,245,246,247] |
Temsirolimus (mTORC1 inhibitor) | Colorectal cancers, Skin cancers, Kidney cancers | CQ, HCQ | ATG7 shRNA | [248,249,250] |
Dactolisib/NVP-BEZ235 (Dual mTOR/Class I PI3K (phosphoinositide 3-kinase) inhibitor) | Kidney cancers, Liver cancers, Blood cancers, Colorectal cancers, Head and neck cancers, Gliomas, Mesotheliomas, Gastric cancers, Rhabdomyosarcomas, Neuroblastomas, Lung cancers | 3-MA, CQ, Baf A1, VPS34 inhibitor (VPS34-IN1) | ATG5 siRNA, BECN1 siRNA | [251,252,253,254,255,256,257,258,259,260] |
Buparlisib/BKM120 (Pan-Class I PI3K inhibitor) | Lung cancers | CQ | - | [261] |
Pictilisib/GDC-0941 (Pan-Class I PI3K inhibitor) | Breast cancers | CQ | ATG5 siRNA, ATG7 siRNA | [262] |
Lapatinib (Dual EGFR/HER2 inhibitor) | Breast cancers, Esophageal cancers | CQ, 3-MA | ATG12 shRNA, ATG5 siRNA, BECN1 siRNA | [200,263,264,265] |
Afatinib (EGFR/HER2/HER4 inhibitor) | Lung cancers | HCQ, 3-MA | - | [266] |
Bortezomib (Proteasome inhibitor) | Breast cancers, Blood cancers, Pancreatic cancers, Cervical cancers, Prostate cancers, Neuroblastomas | 3-MA, HCQ, CQ, Baf A1 | LC3B siRNA, ATG5 siRNA, P62 shRNA, GABARAPL1 shRNA, BECN1 siRNA | [267,268,269,270,271,272,273,274,275,276] |
Carfilzomib (Proteasome inhibitor) | Blood cancers, Neuroblastomas | CQ, HCQ | - | [277,278,279] |
Vemurafenib (B-RAF inhibitor) | Brain cancers, Skin cancers, Thyroid cancers, Colorectal cancers | CQ, HCQ, Baf A1, Lys05 | ATG5 siRNA, ATG5 shRNA, ATG7 siRNA, ATG13 siRNA | [280,281,282,283,284,285,286] |
Trametinib (MEK1/2 (mitogen-activated protein kinase kinase 1/ 2) inhibitor) | Skin cancers, Pancreatic cancers | CQ, HCQ, PIK-III | Inactive dominant-negative ATG4BC74A | [287,288] |
AKTi-1/2 (Dual AKT 1/2 (Protein kinase B 1/ 2) inhibitor) | Ovarian cancers, Liver cancers, Prostate cancers | CQ, Spautin-1, 3-MA, Baf A1 | ATG7 siRNA, ATG5 siRNA, BECN1 siRNA, BECN1 shRNA | [289,290,291] |
AZD5363 (AKT 1/2/3 inhibitor) | Prostate cancers | CQ, 3-MA, Baf A1 | ATG3 siRNA, ATG7 siRNA | [292] |
Tamoxifen (ER (estrogen receptor) inhibitor; anti-estrogenic analog) | Breast cancers | HCQ, Baf A1, 3-MA | ATG7 siRNA, BECN1 siRNA, LAMP3 shRNA, LC3B siRNA, ATG5 siRNA, BECN1 siRNA | [293,294,295,296,297,298,299] |
Imatinib (BCR-ABL (breakpoint cluster region-abelson murine leukemia viral oncogene homolog 1) inhibitor) | Blood cancers, Gastrointestinal cancers, Colorectal cancers | Spautin-1, CQ, HCQ, Quinacrine, Vincristine | ATG7 siRNA, ATG12 siRNA, ATG4B shRNA, BECN1 shRNA, ATG5 shRNA, miR-30a (BECN1 and ATG5 knockdown) | [73,300,301,302,303,304,305,306] |
HDIL-2 (high-dose interleukin-2 immunotherapy) | Liver cancers | CQ | - | [307,308] |
© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
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Ho, C.J.; Gorski, S.M. Molecular Mechanisms Underlying Autophagy-Mediated Treatment Resistance in Cancer. Cancers 2019, 11, 1775. https://doi.org/10.3390/cancers11111775
Ho CJ, Gorski SM. Molecular Mechanisms Underlying Autophagy-Mediated Treatment Resistance in Cancer. Cancers. 2019; 11(11):1775. https://doi.org/10.3390/cancers11111775
Chicago/Turabian StyleHo, Cally J., and Sharon M. Gorski. 2019. "Molecular Mechanisms Underlying Autophagy-Mediated Treatment Resistance in Cancer" Cancers 11, no. 11: 1775. https://doi.org/10.3390/cancers11111775