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Cell Death Dis. 2017 Sep 14;8(9):e3048. doi: 10.1038/cddis.2017.438.

NDRG1 inhibition sensitizes osteosarcoma cells to combretastatin A-4 through targeting autophagy.

Author information

1
Department of Orthopaedics, Yangpu Hospital, Tongji University, Shanghai, China.
2
Department of Orthopaedics, Shanghai General Hospital, School of Medicine Shanghai Jiao Tong University, Shanghai, China.
3
Department of Oncology, Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
4
Shanghai Bone Tumor Institution, Shanghai, China.

Abstract

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.

PMID:
28906492
PMCID:
PMC5636982
DOI:
10.1038/cddis.2017.438
[Indexed for MEDLINE]
Free PMC Article

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