Ivermectin induces cytostatic autophagy by blocking the PAK1/Akt Axis in breast cancer

Cancer Research

Volumn 76, Issue 15, 2016, Pages 4457-4469

  Dou, Qianhui ^a   Chen, Hai Ning ^a   Wang, Kui ^a,b   Yuan, Kefei ^a   Lei, Yunlong ^c   Li, Kai ^a   Lan, Jiang ^a,b   Chen, Yan ^a   Huang, Zhao ^a   Xie, Na ^a   Zhang, Lu ^a   Xiang, Rong ^d   Nice, Edouard C ^e   Wei, Yuquan ^a   Huang, Canhua ^a,b  

^a SICHUAN UNIVERSITY   (China)

^b BEIJING UNIVERSITY OF POSTS AND TELECOMMUNICATIONS   (China)

^c CHONGQING MEDICAL UNIVERSITY   (China)

^d NANKAI UNIVERSITY   (China)

^e MONASH UNIVERSITY   (Australia)

Author keywords

[No Author keywords available]

Indexed keywords

AUTOPHAGY PROTEIN 5; BECLIN 1; BENZYLOXYCARBONYLLEUCYLLEUCYLLEUCINAL; CHLOROQUINE; INITIATION FACTOR 4E BINDING PROTEIN 1; IVERMECTIN; MAMMALIAN TARGET OF RAPAMYCIN; P21 ACTIVATED KINASE 1; PHOSPHATIDYLINOSITOL 3 KINASE; PLACEBO; PROTEIN BCL 2; PROTEIN KINASE B; S6 KINASE; WORTMANNIN; ANTIPARASITIC AGENT; P21 ACTIVATED KINASE; PAK1 PROTEIN, HUMAN;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTINEOPLASTIC ACTIVITY; APOPTOSIS; ARTICLE; AUTOLYSOSOME; AUTOPHAGOSOME; AUTOPHAGY; BREAST CANCER; CANCER INHIBITION; CELL GROWTH; CELL PROLIFERATION; CELL VIABILITY; CLINICAL ARTICLE; CONJUGATION; CONTROLLED STUDY; CYTOSTASIS; DOWN REGULATION; DRUG EFFECT; DRUG MECHANISM; ENZYME INHIBITION; ENZYME PHOSPHORYLATION; FEMALE; HUMAN; HUMAN CELL; IC50; IN VITRO STUDY; IN VIVO STUDY; MOLECULAR DOCKING; MOUSE; NONHUMAN; PRIORITY JOURNAL; PROTEIN CONFORMATION; PROTEIN DEGRADATION; PROTEIN EXPRESSION; PROTEIN PROTEIN INTERACTION; SIGNAL TRANSDUCTION; TRANSCRIPTION REGULATION; TUMOR VOLUME; TUMOR XENOGRAFT; UBIQUITINATION; ANIMAL; BAGG ALBINO MOUSE; GENETICS; METABOLISM; NONOBESE DIABETIC MOUSE; SCID MOUSE; TUMOR CELL LINE;

ANIMALS; ANTIPARASITIC AGENTS; AUTOPHAGY; CELL LINE, TUMOR; FEMALE; HUMANS; IVERMECTIN; MICE; MICE, INBRED BALB C; MICE, INBRED NOD; MICE, SCID; P21-ACTIVATED KINASES;

EID: 84982734850     PISSN: 00085472     EISSN: 15387445     Source Type: Journal    
DOI: 10.1158/0008-5472.CAN-15-2887     Document Type: Article

References (50)

1. Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, et al. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 2013. Available from: http://globocan.iarc.fr.
2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin 2015;65:5-29.
3. Sharon Y, Raz Y, Cohen N, Ben-Shmuel A, Schwartz H, Geiger T, et al. Tumor-derived osteopontin reprograms normal mammary fibroblasts to promote inflammation and tumor growth in breast cancer. Cancer Res 2015;75:963-73.
4. Boya P, Reggiori F, Codogno P. Emerging regulation and functions of autophagy. Nat Cell Biol 2013;15:713-20.
5. Wang K, Liu R, Li J, Mao J, Lei Y, Wu J, et al. Quercetin induces protective autophagy in gastric cancer cells: involvement of Akt-mTOR- and hypoxia-induced factor 1alpha-mediated signaling. Autophagy 2011;7:966-78.
6. Liu R, Li J, Zhang T, Zou L, Chen Y, Wang K, et al. Itraconazole suppresses the growth of glioblastoma through induction of autophagy: involvement of abnormal cholesterol trafficking. Autophagy 2014;10:1241-55.
7. Gewirtz DA. The four faces of autophagy: implications for cancer therapy. Cancer Res 2014;74:647-51.
8. Efeyan A, Comb WC, Sabatini DM. Nutrient-sensing mechanisms and pathways. Nature 2015;517:302-10.
9. He C, Klionsky DJ. Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet 2009;43:67-93.
10. Fulda S, Kogel D. Cell death by autophagy: emerging molecular mechanisms and implications for cancer therapy. Oncogene 2015;34:5105-13.
11. Levine B, Kroemer G. Autophagy in the pathogenesis of disease. Cell 2008;132:27-42.
12. Ikeda H, Omura S. Avermectin biosynthesis. Chem Rev 1997;97:2591-610.
13. Gonzalez Canga A, Sahagun Prieto AM, Jose Diez Liebana M, Martinez NF, Vega MS, Vieitez JJ. The pharmacokinetics and metabolism of ivermectin in domestic animal species. Vet J 2009;179:25-37.
14. Drinyaev VA, Mosin VA, Kruglyak EB, Novik TS, Sterlina TS, Ermakova NV, et al. Antitumor effect of avermectins. Eur J Pharmacol 2004;501:19-23.
15. Hashimoto H, Messerli SM, Sudo T, Maruta H. Ivermectin inactivates the kinase PAK1 and blocks the PAK1-dependent growth of human ovarian cancer and NF2 tumor cell lines. Drug Discov Ther 2009;3:243-6.
16. Sharmeen S, Skrtic M, Sukhai MA, Hurren R, Gronda M, Wang X, et al. The antiparasitic agent ivermectin induces chloride-dependent membrane hyperpolarization and cell death in leukemia cells. Blood 2010;116:3593-603.
17. Melotti A, Mas C, Kuciak M, Lorente-Trigos A, Borges I, Ruiz i Altaba A. The river blindness drug Ivermectin and related macrocyclic lactones inhibit WNT-TCF pathway responses in human cancer. EMBO Mol Med 2014;6:1263-78.
18. Noman MZ, Buart S, Romero P, Ketari S, Janji B, Mari B, et al. Hypoxia-inducible miR-210 regulates the susceptibility of tumor cells to lysis by cytotoxic T cells. Cancer Res 2012;72:4629-41.
19. Bai L, Wang S. Targeting apoptosis pathways for new cancer therapeutics. Annu Rev Med 2014;65:139-55.
20. Yang XH, Sladek TL, Liu X, Butler BR, Froelich CJ, Thor AD. Reconstitution of caspase 3 sensitizes MCF-7 breast cancer cells to doxorubicin- and etoposide-induced apoptosis. Cancer Res 2001;61:348-54.
21. Blanc C, Deveraux QL, Krajewski S, Janicke RU, Porter AG, Reed JC, et al. Caspase-3 is essential for procaspase-9 processing and cisplatin-induced apoptosis of MCF-7 breast cancer cells. Cancer Res 2000;60:4386-90.
22. Klauschen F, Wienert S, Schmitt WD, Loibl S, Gerber B, Blohmer JU, et al. Standardized Ki67 diagnostics using automated scoring-clinical validation in the GeparTrio Breast Cancer Study. Clin Cancer Res 2015;21:3651-7.
23. Kim Y, Kim Y-S, Kim DE, Lee JS, Song JH, Kim H-G, et al. BIX-01294 induces autophagy-associated cell death via EHMT2/G9a dysfunction and intracellular reactive oxygen species production. Autophagy 2014;9:2126-39.
24. Klionsky DJ, Abdelmohsen K, Abe A, Abedin MJ, Abeliovich H, Acevedo Arozena A, et al. Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 2016;12:1-222.
25. Wu YT, Tan HL, Shui G, Bauvy C, Huang Q, Wenk MR, et al. Dual role of 3-methyladenine in modulation of autophagy via different temporal patterns of inhibition on class I and III phosphoinositide 3-kinase. J Biol Chem 2010;285:10850-61.
26. Schmelzle T, Hall MN. TOR, a central controller of cell growth. Cell 2000;103:253-62.
27. Bodine SC, Stitt TN, Gonzalez M, Kline WO, Stover GL, Bauerlein R, et al. Akt/mTOR pathway is a crucial regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo. Nat Cell Biol 2001;3:1014-9.
28. Fu L, Zhang S, Zhang L, Tong X, Zhang J, Zhang Y, et al. Systems biology network-based discovery of a small molecule activator BL-AD008 targeting AMPK/ZIPK and inducing apoptosis in cervical cancer. Oncotarget 2015;6:8071-88.
29. Higuchi M, Onishi K, Kikuchi C, Gotoh Y. Scaffolding function of PAK in the PDK1-Akt pathway. Nat Cell Biol 2008;10:1356-64.
30. Kumar R, Gururaj AE, Barnes CJ. p21-activated kinases in cancer. Nat Rev Cancer 2006;6:459-71.
31. Dummler B, Ohshiro K, Kumar R, Field J. Pak protein kinases and their role in cancer. Cancer Metastasis Rev 2009;28:51-63.
32. Zhang Z, Bao M, Lu N, Weng L, Yuan B, Liu YJ. The E3 ubiquitin ligase TRIM21 negatively regulates the innate immune response to intracellular double-stranded DNA. Nat Immunol 2013;14:172-8.
33. Jin L, Feng X, Rong H, Pan Z, Inaba Y, Qiu L, et al. The antiparasitic drug ivermectin is a novel FXR ligand that regulates metabolism. Nat Commun 2013;4:1937.
34. Kenific CM, Debnath J. Cellular and metabolic functions for autophagy in cancer cells. Trends Cell Biol 2015;25:37-45.
35. Sy LK, Yan SC, Lok CN, Man RY, Che CM. Timosaponin A-III induces autophagy preceding mitochondria-mediated apoptosis in HeLa cancer cells. Cancer Res 2008;68:10229-37.
36. Marino G, Niso-Santano M, Baehrecke EH, Kroemer G. Self-consumption: the interplay of autophagy and apoptosis. Nat Rev Mol Cell Biol 2014;15:81-94.
37. Ghobrial IM, Witzig TE, Adjei AA. Targeting apoptosis pathways in cancer therapy. CA Cancer J Clin 2005;55:178-94.
38. de Bruin EC, Medema JP. Apoptosis and non-apoptotic deaths in cancer development and treatment response. Cancer Treat Rev 2008;34:737-49.
39. Hippert MM, O'Toole PS, Thorburn A. Autophagy in cancer: good, bad, or both? Cancer Res 2006;66:9349-51.
40. Lefranc F, Facchini V, Kiss R. Proautophagic drugs: a novel means to combat apoptosis-resistant cancers, with a special emphasis on glioblastomas. Oncologist 2007;12:1395-403.
41. Sharma K, Goehe RW, Di X, Hicks MA II, Torti SV, Torti FM, et al. 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 2014;10:2346-61.
42. Shinojima N, Yokoyama T, Kondo Y, Kondo S. Roles of the Akt/mTOR/p70S6K and ERK1/2 signaling pathways in curcumin-induced autophagy. Autophagy 2007;3:635-7.
43. Vadlamudi RK, Adam L, Wang RA, Mandal M, Nguyen D, Sahin A, et al. Regulatable expression of p21-activated kinase-1 promotes anchorage-independent growth and abnormal organization of mitotic spindles in human epithelial breast cancer cells. J Biol Chem 2000;275:36238-44.
44. Bokoch GM. Biology of the p21-activated kinases. Annu Rev Biochem 2003;72:743-81.
45. Holm C, Rayala S, Jirstrom K, Stal O, Kumar R, Landberg G. Association between Pak1 expression and subcellular localization and tamoxifen resistance in breast cancer patients. J Natl Cancer Inst 2006;98:671-80.
46. Siu MK, Wong ES, Chan HY, Kong DS, Woo NW, Tam KF, et al. Differential expression and phosphorylation of Pak1 and Pak2 in ovarian cancer: effects on prognosis and cell invasion. Int J Cancer 2010;127:21-31.
47. Zhu G, Wang Y, Huang B, Liang J, Ding Y, Xu A, et al. A Rac1/PAK1 cascade controls beta-catenin activation in colon cancer cells. Oncogene 2012;31:1001-12.
48. Rayala SK, Molli PR, Kumar R. Nuclear p21-activated kinase 1 in breast cancer packs off tamoxifen sensitivity. Cancer Res 2006;66:5985-8.
49. Zwart W, Griekspoor A, Berno V, Lakeman K, Jalink K, Mancini M, et al. PKA-induced resistance to tamoxifen is associated with an altered orientation of ERalpha towards co-activator SRC-1. EMBO J 2007;26:3534-44.
50. Kwon Y-J, Leibovitch BA, Zeng L, Mezei M, Christova R, Yang S, et al. Selamectin and ivermectin are small molecule inhibitors that interfere with Sin3A-PAH2 function and exert anti-tumor activity in triple-negative breast cancer. Cancer Res 2014;74:807-07.