Oncotarget

Research Papers:

Obatoclax impairs lysosomal function to block autophagy in cisplatin-sensitive and -resistant esophageal cancer cells

Le Yu, William K.K. Wu, Chunping Gu, Desheng Zhong, Xuyan Zhao, Yi Kong, Qinghuan Lin, Matthew T.V. Chan, Zhitao Zhou and Shuwen Liu _

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Oncotarget. 2016; 7:14693-14707. https://doi.org/10.18632/oncotarget.7492

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Abstract

Le Yu1, William K.K. Wu2,3, Chunping Gu1,4, Desheng Zhong1, Xuyan Zhao1, Yi Kong1, Qinghuan Lin1, Matthew T.V. Chan2, Zhitao Zhou5, Shuwen Liu1

1State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China

2Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong, China

3State Key Laboratory of Digestive Diseases, LKS Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China

4Nanfang Hospital, Southern Medical University, Guangzhou, China

5Electron Microscopy Laboratory, Southern Medical University, Guangzhou, China

Correspondence to:

Shuwen Liu, e-mail: [email protected]

Keywords: autophagy, lysosome, obatoclax, cisplatin resistance, cathepsin

Received: June 08, 2015     Accepted: December 29, 2015     Published: February 19, 2016

ABSTRACT

Obatoclax, a pan-inhibitor of anti-apoptotic Bcl-2 proteins, exhibits cytotoxic effect on cancer cells through both apoptosis-dependent and -independent pathways. Here we show that obatoclax caused cytotoxicity in both cisplatin-sensitive and -resistant esophageal cancer cells. Although obatoclax showed differential apoptogenic effects in these cells, it consistently blocked autophagic flux, which was evidenced by concomitant accumulation of LC3-II and p62. Obatoclax was trapped in lysosomes and induced lysosome clustering. Obatoclax also substantially reduced the expression of lysosomal cathepsins B, D and L. Moreover, cathepsin knockdown was sufficient to induce cytotoxicity, connecting lysosomal function to cell viability. Consistent with the known function of autophagy, obatoclax caused the accumulation of polyubiquitinated proteins and showed synergy with proteasome inhibition. Taken together, our studies unveiled impaired lysosomal function as a novel mechanism whereby obatoclax mediates its cytotoxic effect in esophageal cancer cells.


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