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

TI  - Nonsteroidal Anti-inflammatory Drugs Sensitize CD44-Overexpressing Cancer  Cells to Hsp90 Inhibitor Through Autophagy Activation
T2  - Oncology Research

PY  - 2019
VL  - 27
IS  - 7
SN  - 1555-3906

AB  - 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 (CD44<sup>high</sup>K562) 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 CD44<sup>high</sup>K562 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 CD44<sup>high</sup>K562 cells. In addition, 
treatment of CD44<sup>high</sup>K562 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 
CD44<sup>high</sup>K562 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.
KW  - CD44; Hsp90 inhibitor; Nonsteroidal anti-inflammatory drugs (NSAIDs);  Stemness-related markers; Autophagy

DO  - 10.3727/096504019X15517850319579