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.
Highlights
Autophagy is an evolutionarily conserved, homeostatic process that components of the cell are degraded to maintain essential activity and viability as a response to numerous stimuli.[1]
To investigate the effect of Combretastatin A-4 (CA-4) on autophagy and the role of autophagy in determining the sensitivity of OS cells to this agent, we first examined the activity of autophagy in OS cells treated with CA-4
LC3-II levels were further elevated in the presence of CQ, a lysosome inhibitor that blocks the fusion of autophagosomes and lysosomes and LC3-II degradation, indicating an increase of autophagic flux in CA-4 treated OS cells (Figures 1d and e)
Summary
Autophagy is an evolutionarily conserved, homeostatic process that components of the cell are degraded to maintain essential activity and viability as a response to numerous stimuli.[1]. Because of autophagy major role in cell survival during unfavorable conditions, targeting autophagy may be a reasonable anticancer strategy that improves the efficacy of many standard of care agents Consistent with this viewpoint, growing evidence shows that autophagy inhibitors like chloroquine (CQ) or 3-methyladenine (3-MA) sensitize cancer cells to chemotherapy treatments like DNA-damage agent doxorubicin,[2] DNA alkylating agent cisplatin,[3] microtubuletargeting agent vincristine,[4] anti-angiogenic agent bevacizumab[5] and tyrosine kinase receptor inhibitor imatinib.[6] understanding how autophagic machinery regulates chemotherapy sensitivity is crucial for cancer therapy. Jung et al.[24] found that hypoxia- and RA-inducible NDRG1 expression is the response for doxorubicin and RA resistance, and the selective interruption of NDRG1 signaling may prove therapeutically useful in hepatocellular carcinoma cells These findings indicated that NDRG1 may be developed as an attractive candidate for targeted therapy. Our findings provide clues for developing more effective cancer therapeutic strategies by the concomitant treatment with CA-4 and clinical available autophagy inhibitors
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