Inhibition of autophagy enhances cisplatin-induced apoptosis in the MG63 human osteosarcoma cell line

Zhang,Zhicai; Shao,Zengwu; Xiong,Liming; Yang,Shuhua

doi:10.3892/ol.2015.3692

Inhibition of autophagy enhances cisplatin-induced apoptosis in the MG63 human osteosarcoma cell line

Authors:
- Zhicai Zhang
- Zengwu Shao
- Liming Xiong
- Shuhua Yang
View Affiliations

Affiliations: Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China
Published online on: September 10, 2015 https://doi.org/10.3892/ol.2015.3692
Pages: 2941-2946

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

Autophagy is a significant catabolic process that allows the renewal of intracellular organelles, through which cells are able to maintain homeostasis. In addition, autophagy may be associated with the carcinogenesis of osteosarcoma (OS). Cisplatin (CDDP) is an alkylating agent that is commonly used as an anticancer therapy. However, the pathways underlying the effects of CDDP remain to be elucidated. The present study demonstrated that 3‑methyladenine (3‑MA), an inhibitor of autophagy, was able to increase the proliferation inhibition ratios of MG63 human OS cells when used in combination with CDDP. Furthermore, MG63 cells produced significantly more microtubule‑associated protein light chain 3II (LC3II), a widely used marker for monitoring autophagy, following CDDP treatment. Treatment with 3‑MA was observed to inhibit these changes. Similarly, MG63 cells co‑treated with 3‑MA and CDDP demonstrated increased sensitivity to CDDP‑induced apoptosis, compared with those exposed to CDDP alone. The present study revealed variation in the expression of LC3II and caspase‑3 activity following treatment with certain drugs. The results of the present study suggest that CDDP may be capable of inducing apoptosis and autophagy, and that autophagy may be able to inhibit apoptosis in MG63 cells. Therefore, downregulation of autophagy may increase the chemotherapeutic sensitivity of MG63 cells to CDDP.

View Figures

View References

1	Desandes E: Survival from adolescent cancer. Cancer Treat Rev. 33:609–615. 2007. View Article : Google Scholar : PubMed/NCBI
2	Biermann JS, Adkins D, Benjamin R, Brigman B, Chow W, Conrad EU III, Frassica D, Frassica FJ, George S, Healey JH, et al: National Comprehensive Cancer Network: Bone cancer. J Natl Compr Canc Netw. 5:420–437. 2007.PubMed/NCBI
3	Sakamoto A and Iwamoto Y: Current status and perspectives regarding the treatment of osteo-sarcoma: Chemotherapy. Rev Recent Clin Trials. 3:228–231. 2008. View Article : Google Scholar : PubMed/NCBI
4	Yamamoto N and Tsuchiya H: Chemotherapy for osteosarcoma - where does it come from? What is it? Where is it going? Expert Opin Pharmacother. 14:2183–2193. 2013. View Article : Google Scholar : PubMed/NCBI
5	Shen HM and Tergaonkar V: NFkappaB signaling in carcinogenesis and as a potential molecular target for cancer therapy. Apoptosis. 14:348–363. 2009. View Article : Google Scholar : PubMed/NCBI
6	Monastyrska I and Klionsky DJ: Autophagy in organelle homeostasis: Peroxisome turnover. Mol Aspects Med. 27:483–494. 2006. View Article : Google Scholar : PubMed/NCBI
7	Shintani T and Klionsky DJ: Autophagy in health and disease: A double-edged sword. Science. 306:990–995. 2004. View Article : Google Scholar : PubMed/NCBI
8	Gewirtz DA: Autophagy as a mechanism of radiation sensitization in breast tumor cells. Autophagy. 3:249–250. 2007. View Article : Google Scholar : PubMed/NCBI
9	Lemasters JJ, Nieminen AL, Qian T, Trost LC, Elmore SP, Nishimura Y, Crowe RA, Cascio WE, Bradham CA, Brenner DA, et al: The mitochondrial permeability transition in cell death: A common mechanism in necrosis, apoptosis and autophagy. Biochim Biophys Acta. 1366:177–196. 1998. View Article : Google Scholar : PubMed/NCBI
10	Zhang Z, Shao Z, Xiong L, Che B, Deng C and Xu W: Expression of Beclin1 in osteosarcoma and the effects of down-regulation of autophagy on the chemotherapeutic sensitivity. J Huazhong Univ Sci Technolog Med Sci. 29:737–740. 2009. View Article : Google Scholar : PubMed/NCBI
11	Wu J, Dang Y, Su W, Liu C, Ma H, Shan Y, Pei Y, Wan B, Guo J and Yu L: Molecular cloning and characterization of rat LC3A and LC3B - two novel markers of autophagosome. Biochem Biophys Res Commun. 339:437–442. 2006. View Article : Google Scholar : PubMed/NCBI
12	Seki K, Yoshikawa H, Shiiki K, Hamada Y, Akamatsu N and Tasaka K: Cisplatin (CDDP) specifically induces apoptosis via sequential activation of caspase-8, −3 and −6 in osteosarcoma. Cancer Chemother Pharmacol. 45:199–206. 2000. View Article : Google Scholar : PubMed/NCBI
13	Suzuki K, Kubota Y, Sekito T and Ohsumi Y: Hierarchy of Atg proteins in pre-autophagosomal structure organization. Genes Cells. 12:209–218. 2007. View Article : Google Scholar : PubMed/NCBI
14	Halpain S and Dehmelt L: The MAP1 family of microtubule-associated proteins. Genome Biol. 7:2242006. View Article : Google Scholar : PubMed/NCBI
15	Nooter K and Stoter G: Molecular mechanisms of multidrug resistance in cancer chemotherapy. Pathol Res Pract. 192:768–780. 1996. View Article : Google Scholar : PubMed/NCBI
16	Ogawa M: Anticancer drugs and pharmacologic actions. Nihon Rinsho. 55:1017–1023. 1997.(In Japanese). PubMed/NCBI
17	Park YP, Kim KD, Kang SH, Yoon Y, Park JW, Kim JW and Lee HG: Human telomerase reverse transcriptase (hTERT): A target molecule for the treatment of cisplatin-resistant tumors. Korean J Lab Med. 28:430–437. 2008. View Article : Google Scholar : PubMed/NCBI
18	Kanzawa T, Germano IM, Komata T, Ito H, Kondo Y and Kondo S: Role of autophagy in temozolomide-induced cytotoxicity for malignant glioma cells. Cell Death Differ. 11:448–457. 2004. View Article : Google Scholar : PubMed/NCBI
19	Opipari AW Jr, Tan L, Boitano AE, Sorenson DR, Aurora A and Liu JR: Resveratrol-induced autophagocytosis in ovarian cancer cells. Cancer Res. 64:696–703. 2004. View Article : Google Scholar : PubMed/NCBI
20	Xie Z and Klionsky DJ: Autophagosome formation: Core machinery and adaptations. Nat Cell Biol. 9:1102–1109. 2007. View Article : Google Scholar : PubMed/NCBI
21	Tanida I, Ueno T and Kominami E: LC3 conjugation system in mammalian autophagy. Int J Biochem Cell Biol. 36:2503–2518. 2004. View Article : Google Scholar : PubMed/NCBI
22	Yang YP, Liang ZQ, Gu ZL and Qin ZH: Molecular mechanism and regulation of autophagy. Acta Pharmacol Sin. 26:1421–1434. 2005. View Article : Google Scholar : PubMed/NCBI
23	Bauvy C, Gane P, Arico S, Codogno P and Ogier-Denis E: Autophagy delays sulindac sulfide-induced apoptosis in the human intestinal colon cancer cell line HT-29. Exp Cell Res. 268:139–149. 2001. View Article : Google Scholar : PubMed/NCBI
24	Herman-Antosiewicz A, Johnson DE and Singh SV: Sulforaphane causes autophagy to inhibit release of cytochrome c and apoptosis in human prostate cancer cells. Cancer Res. 66:5828–5835. 2006. View Article : Google Scholar : PubMed/NCBI
25	Sui X, Kong N, Ye L, Han W, Zhou J, Zhang Q, He C and Pan H: p38 and JNK MAPK pathways control the balance of apoptosis and autophagy in response to chemotherapeutic agents. Cancer Lett. 344:174–179. 2014. View Article : Google Scholar : PubMed/NCBI