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Nonsteroidal Anti-inflammatory Drugs Sensitize CD44-Overexpressing Cancer Cells to Hsp90 Inhibitor Through Autophagy Activation

Hyun-Jung Moon,1 So-Young Park,1 Su-Hoon Lee, Chi-Dug Kang, Sun-Hee Kim

Department of Biochemistry, Pusan National University School of Medicine, Yangsan, South Korea

Oncology Research 2019, 27(7), 835-847. https://doi.org/10.3727/096504019X15517850319579

Abstract

Recently, novel therapeutic strategies have been designed with the aim of killing cancer stem-like cells (CSCs), and considerable interest has been generated in the development of specific therapies that target stemnessrelated marker of CSCs. In this study, nonsteroidal anti-inflammatory drugs (NSAIDs) significantly potentiated Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG)-mediated cytotoxicity through apoptotic and autophagic cell death induction, but COX-2-inhibitory function was not required for NSAIDinduced autophagy in CD44-overexpressing human chronic myeloid leukemia K562 (CD44highK562) cells. Importantly, we found that treatment with NSAIDs resulted in a dose-dependent increase in LC3-II level and decrease in p62 level and simultaneous reduction in multiple stemness-related markers including CD44, Oct4, c-Myc, and mutant p53 (mutp53) in CD44highK562 cells, suggesting that NSAIDs could induce autophagy, which might mediate degradation of stemness-related marker proteins. Activation of AMPK and inhibition of Akt/mTOR/p70S6K/4EBP1 participated in NSAID-induced autophagy in CD44highK562 cells. In addition, treatment of CD44highK562 cells with NSAIDs inhibited expression of HSF1/Hsps, which resulted in suppression of 17-AAG-induced activation of Hsp70, leading to reversal of 17-AAG resistance and sensitization of CD44highK562 cells to 17-AAG by NSAIDs. In conclusion, combining NSAIDs with Hsp90 inhibitor may offer one of the most promising strategies for eradication of CD44-overexpressing CSCs.

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APA Style
Moon, H., Park, 1.S., Lee, 1.S., Kang, C., Kim, S. (2019). Nonsteroidal anti-inflammatory drugs sensitize cd44-overexpressing cancer cells to hsp90 inhibitor through autophagy activation. Oncology Research, 27(7), 835-847. https://doi.org/10.3727/096504019X15517850319579
Vancouver Style
Moon H, Park 1S, Lee 1S, Kang C, Kim S. Nonsteroidal anti-inflammatory drugs sensitize cd44-overexpressing cancer cells to hsp90 inhibitor through autophagy activation. Oncol Res. 2019;27(7):835-847 https://doi.org/10.3727/096504019X15517850319579
IEEE Style
H. Moon, 1.S. Park, 1.S. Lee, C. Kang, and S. Kim "Nonsteroidal Anti-inflammatory Drugs Sensitize CD44-Overexpressing Cancer Cells to Hsp90 Inhibitor Through Autophagy Activation," Oncol. Res., vol. 27, no. 7, pp. 835-847. 2019. https://doi.org/10.3727/096504019X15517850319579



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