Open AccessNDRG1 inhibition sensitizes osteosarcoma cells to combretastatin A-4 through targeting autophagy
Author(s) -
Hongsheng Wang,
Wen Li,
Jing Xu,
Tao Zhang,
Dongqing Zuo,
Zifei Zhou,
Binhui Lin,
Gangyang Wang,
Zhuoying Wang,
Wei Sun,
Mengxiong Sun,
ShiMin Chang,
Zhengdong Cai,
Yingqi Hua
Publication year - 2017
Publication title -
cell death and disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.482
H-Index - 111
ISSN - 2041-4889
DOI - 10.1038/cddis.2017.438
Subject(s) - autophagy , lysosome , gene knockdown , cancer research , chloroquine , autophagosome , apoptosis , downregulation and upregulation , programmed cell death , microbiology and biotechnology , cancer cell , chemistry , biology , cancer , immunology , biochemistry , enzyme , gene , genetics , malaria
Combretastatin A-4 (CA-4), a tubulin-depolymerizing agent, shows promising antitumor efficacy and has been under several clinical trials in solid tumors for 10 years. Autophagy has an important pro-survival role in cancer therapy, thus targeting autophagy may improve the efficacy of antitumor agents. N-myc downstream-regulated gene 1 (NDRG1) is a significant stress regulatory gene, which mediates cell survival and chemoresistance. Here we reported that CA-4 could induce cell-protective autophagy, and combination treatment of CA-4 and autophagy inhibitor chloroquine (CQ) exerted synergistic cytotoxic effect on human osteosarcoma (OS) cells. Meanwhile, CA-4 or CQ could increase the expression of NDRG1 independently. We further performed mechanistic study to explore how CA-4 and CQ regulate the expression of NDRG1. Using luciferase reporter assay, we found that CA-4 transcriptionally upregulated NDRG1 expression, whereas CQ triggered colocalization of NDRG1 and lysosome, which subsequently prevented lysosome-dependent degradation of NDRG1. Further, we showed that knockdown of NDRG1 caused the defect of lysosomal function, which accumulated LC3-positive autophagosomes by decreasing their fusion with lysosomes. Moreover, NDRG1 inhibition increased apoptosis in response to combination treatment with CA-4 and CQ. Taken together, our study revealed abrogation of NDRG1 expression sensitizes OS cells to CA-4 by suppression of autophagosome–lysosome fusion. These results provide clues for developing more effective cancer therapeutic strategies by the concomitant treatment with CA-4 and clinical available autophagy inhibitors.