Cabazitaxel-induced autophagy via the PI3K/Akt/mTOR pathway contributes to A549 cell death

Huo,Ruichao; Wang,Lili; Liu,Peijuan; Zhao,Yong; Zhang,Caiqin; Bai,Bing; Liu,Xueying; Shi,Changhong; Wei,Sanhua; Zhang,Hai

doi:10.3892/mmr.2016.5648

Cabazitaxel-induced autophagy via the PI3K/Akt/mTOR pathway contributes to A549 cell death

Authors:
- Ruichao Huo
- Lili Wang
- Peijuan Liu
- Yong Zhao
- Caiqin Zhang
- Bing Bai
- Xueying Liu
- Changhong Shi
- Sanhua Wei
- Hai Zhang
View Affiliations

Affiliations: College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi 712100, P.R. China, Laboratory Animal Center, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China, Department of Medicinal Chemistry, Fourth Military Medical University, Xi'an, Shaanxi 710032, P.R. China, Department of Laboratory and Research Center, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710038, P.R. China
Published online on: August 19, 2016 https://doi.org/10.3892/mmr.2016.5648
Pages: 3013-3020
Copyright: © Huo et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Cabazitaxel has been used to treat castration-resistant prostate cancer since its approval by the US Food and Drug Administration in 2010. However, whether cabazitaxel may inhibit the proliferation of other tissue‑derived cancer cells, and its underlying mechanism, remains unknown. In the present study, the A549 lung adenocarcinoma cancer cell line was exposed to cabazitaxel, in order to investigate its cytotoxic effect and determine the underlying mechanism. The results demonstrated that cabazitaxel was able to induce autophagy in A549 cells, as evidenced by the formation of autophagosomes, upregulated LC3‑II expression and increased LC3 puncta. Cabazitaxel‑induced autophagy had a cytotoxic effect on A549 cells, as evidenced by the induction of cell death and cell cycle arrest at G2/M phase, which was independent of the apoptotic pathway. Furthermore, transfection with Beclin1 small interfering RNA and treatment with the autophagy inhibitor 3‑methyladenine protected cells from cabazitaxel‑induced cell death, thus confirming that cabazitaxel‑induced autophagy contributed to A549 cell death. In addition, cabazitaxel targeted the phosphoinositide 3‑kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway to induce autophagy, as indicated by reduced phosphorylation of Akt and mTOR. In conclusion, the present study demonstrated that cabazitaxel exerts a cytotoxic effect on A549 cells by acting on the PI3K/Akt/mTOR pathway to promote autophagic cell death. This result supports the potential use of cabazitaxel as a chemotherapeutic agent for the treatment of lung cancer.

View Figures

View References

1	McLeod IX, Jia W and He YW: The contribution of autophagy to lymphocyte survival and homeostasis. Immunol Rev. 249:195–204. 2012. View Article : Google Scholar : PubMed/NCBI
2	Wang Y and Qin ZH: Coordination of autophagy with other cellular activities. Acta Pharmacol Sin. 34:585–594. 2013. View Article : Google Scholar : PubMed/NCBI
3	Janku F, McConkey DJ, Hong DS and Kurzrock R: Autophagy as a target for anticancer therapy. Nat Rev Clin Oncol. 8:528–539. 2011. View Article : Google Scholar : PubMed/NCBI
4	Deretic V: Autophagy in infection. Curr Opin Cell Biol. 22:252–262. 2010. View Article : Google Scholar : PubMed/NCBI
5	Jiang S, Dupont N, Castillo EF and Deretic V: Secretory versus degradative autophagy: Unconventional secretion of inflammatory mediators. J Innate Immun. 5:471–479. 2013. View Article : Google Scholar : PubMed/NCBI
6	Janda E, Isidoro C, Carresi C and Mollace V: Defective autophagy in Parkinson's disease: Role of oxidative stress. Mol Neurobiol. 46:639–661. 2012. View Article : Google Scholar : PubMed/NCBI
7	Ren SY and Xu X: Role of autophagy in metabolic syndrome-associated heart disease. Biochim Biophys Acta. 1852:225–231. 2015. View Article : Google Scholar
8	White E and DiPaola RS: The double-edged sword of autophagy modulation in cancer. Clin Cancer Res. 15:5308–5316. 2009. View Article : Google Scholar : PubMed/NCBI
9	Galluzzi L, Vicencio JM, Kepp O, Tasdemir E, Maiuri MC and Kroemer G: To die or not to die: That is the autophagic question. Curr Mol Med. 8:78–91. 2008. View Article : Google Scholar : PubMed/NCBI
10	Shen S, Kepp O and Kroemer G: The end of autophagic cell death? Autophagy. 8:1–3. 2012. View Article : Google Scholar
11	Kaminskyy V, Abdi A and Zhivotovsky B: A quantitative assay for the monitoring of autophagosome accumulation in different phases of the cell cycle. Autophagy. 7:83–90. 2011. View Article : Google Scholar
12	Jiang P and Mizushima N: LC3- and p62-based biochemical methods for the analysis of autophagy progression in mammalian cells. Methods. 75:13–18. 2015. View Article : Google Scholar
13	Torrisi R, Balduzzi A, Ghisini R, Rocca A, Bottiglieri L, Giovanardi F, Veronesi P, Luini A, Orlando L, Viale G, et al: Tailored preoperative treatment of locally advanced triple negative (hormone receptor negative and HER2 negative) breast cancer with epirubicin, cisplatin, and infusional fluorouracil followed by weekly paclitaxel. Cancer Chemother Pharmacol. 62:667–672. 2008. View Article : Google Scholar
14	Kaufmann SH and Earnshaw WC: Induction of apoptosis by cancer chemotherapy. Exp Cell Res. 256:42–49. 2000. View Article : Google Scholar : PubMed/NCBI
15	Yang ZJ, Chee CE, Huang S and Sinicrope FA: The role of autophagy in cancer: Therapeutic implications. Mol Cancer Ther. 10:1533–1541. 2011. View Article : Google Scholar : PubMed/NCBI
16	Guo WJ, Zhang YM, Zhang L, Huang B, Tao FF, Chen W, Guo ZJ, Xu Q and Sun Y: Novel monofunctional platinum (II) complex Mono-Pt induces apoptosis-independent autophagic cell death in human ovarian carcinoma cells, distinct from cisplatin. Autophagy. 9:996–1008. 2013. View Article : Google Scholar : PubMed/NCBI
17	Liu XW, Cai TY, Zhu H, Cao J, Su Y, Hu YZ, He QJ and Yang B: Q6, a novel hypoxia-targeted drug, regulates hypoxia-inducible factor signaling via an autophagy-dependent mechanism in hepatocellular carcinoma. Autophagy. 10:111–122. 2014. View Article : Google Scholar
18	Dragowska WH, Weppler SA, Wang JC, Wong LY, Kapanen AI, Rawji JS, Warburton C, Qadir MA, Donohue E, Roberge M, et al: Induction of autophagy is an early response to gefitinib and a potential therapeutic target in breast cancer. PLoS One. 8:e765032013. View Article : Google Scholar : PubMed/NCBI
19	Zhou J, Hu H, Long J, Wan F, Li L, Zhang S, Shi YE and Chen Y: Vitexin 6, a novel lignan, induces autophagy and apoptosis by activating the Jun N-terminal kinase pathway. Anticancer Drugs. 24:928–936. 2013. View Article : Google Scholar : PubMed/NCBI
20	Vrignaud P, Sémiond D, Lejeune P, Bouchard H, Calvet L, Combeau C, Riou JF, Commerçon A, Lavelle F and Bissery MC: Preclinical antitumor activity of cabazitaxel, a semisynthetic taxane active in taxane-resistant tumors. Clin Cancer Res. 19:2973–2983. 2013. View Article : Google Scholar : PubMed/NCBI
21	Azarenko O, Smiyun G, Mah J, Wilson L and Jordan MA: Antiproliferative mechanism of action of the novel taxane cabazitaxel as compared with the parent compound docetaxel in MCF7 breast cancer cells. Mol Cancer Ther. 13:2092–2103. 2014. View Article : Google Scholar : PubMed/NCBI
22	Liu F, Liu D, Yang Y and Zhao S: Effect of autophagy inhibition on chemotherapy-induced apoptosis in A549 lung cancer cells. Oncol Lett. 5:1261–1265. 2013.PubMed/NCBI
23	Yu D, Makkar G, Dong T, Strickland DK, Sarkar R and Monahan TS: MARCKS signaling differentially regulates vascular smooth muscle and endothelial cell proliferation through a KIS-, p27kip1- dependent mechanism. PLoS One. 10:e01413972015. View Article : Google Scholar : PubMed/NCBI
24	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)). Method Methods. 25:402–408. 2001. View Article : Google Scholar
25	Sharma K, Le N, Alotaibi M and Gewirtz DA: Cytotoxic autophagy in cancer therapy. Int J Mol Sci. 15:10034–10051. 2014. View Article : Google Scholar : PubMed/NCBI
26	Kung CP, Budina A, Balaburski G, Bergenstock MK and Murphy M: Autophagy in tumor suppression and cancer therapy. Crit Rev Eukaryot Gene Expr. 21:71–100. 2011. View Article : Google Scholar : PubMed/NCBI
27	Shen HM and Codogno P: Autophagic cell death: Loch Ness monster or endangered species? Autophagy. 7:457–465. 2011. View Article : Google Scholar
28	Choi KS: Autophagy and cancer. Exp Mol Med. 44:109–120. 2012. View Article : Google Scholar : PubMed/NCBI
29	Mihaylova MM and Shaw RJ: The AMPK signalling pathway coordinates cell growth, autophagy and metabolism. Nat Cell Biol. 13:1016–1023. 2011. View Article : Google Scholar : PubMed/NCBI
30	Høyer-Hansen M and Jäättelä M: AMP-activated protein kinase: A universal regulator of autophagy? Autophagy. 3:381–383. 2007. View Article : Google Scholar : PubMed/NCBI
31	Shi WY, Xiao D, Wang L, Dong LH, Yan ZX, Shen ZX, Chen SJ, Chen Y and Zhao WL: Therapeutic metformin/AMPK activation blocked lymphoma cell growth via inhibition of mTOR pathway and induction of autophagy. Cell Death Dis. 3:e2752012. View Article : Google Scholar : PubMed/NCBI
32	Corcelle E, Djerbi N, Mari M, Nebout M, Fiorini C, Fénichel P, Hofman P, Poujeol P and Mograbi B: Control of the autophagy maturation step by the MAPK ERK and p38: Lessons from environmental carcinogens. Autophagy. 3:57–59. 2007. View Article : Google Scholar
33	Li Y, Zhang P, Qiu F, Chen L, Miao C, Li J, Xiao W and Ma E: Inactivation of PI3K/Akt signaling mediates proliferation inhibition and G2/M phase arrest induced by andrographolide in human glioblastoma cells. Life Sci. 90:962–967. 2012. View Article : Google Scholar : PubMed/NCBI
34	Takeuchi H, Kondo Y, Fujiwara K, Kanzawa T, Aoki H, Mills GB and Kondo S: Synergistic augmentation of rapamycin-induced autophagy in malignant glioma cells by phosphatidylinositol 3-kinase/protein kinase B inhibitors. Cancer Res. 65:3336–3346. 2005.PubMed/NCBI
35	Paglin S, Lee NY, Nakar C, Fitzgerald M, Plotkin J, Deuel B, Hackett N, McMahill M, Sphicas E, Lampen N and Yahalom J: Rapamycin-sensitive pathway regulates mitochondrial membrane potential, autophagy, and survival in irradiated MCF-7 cells. Cancer Res. 65:11061–11070. 2005. View Article : Google Scholar : PubMed/NCBI
36	Fumarola C, Bonelli MA, Petronini PG and Alfieri RR: Targeting PI3K/AKT/mTOR pathway in non small cell lung cancer. Biochem Pharmacol. 90:197–207. 2014. View Article : Google Scholar : PubMed/NCBI