Hsp90 inhibitor 17-AAG inhibits stem cell-like properties and chemoresistance in osteosarcoma cells via the Hedgehog signaling pathway

Abstract

Multiple drug resistance is a major obstacle to the successful treatment of osteosarcoma (OS). Recent studies have demonstrated that a subset of cells, referred to as OS stem cells (OSCs), play a crucial role in the acquisition of multiple drug resistance. Therefore, an improved understanding of OS biology and pathogenesis is required to advance the development of targeted therapies aimed at eradicating this particular subset of cells in order to reverse acquired chemoresistance in OS. The aim of the present study was to assess the anti-OSC effects of 17-AAG and determine the underlying molecular mechanism. Heat shock protein 90 expression was found to be increased in sarcosphere cells and was positively associated with cancer stem cell characteristics. In addition, 17-AAG was able to suppress the stem cell-like phenotype of OS cells. Mechanistically, 17-AAG inhibited OSC-like properties and chemoresistance through glycogen synthase kinase (GSK) 3β inactivation-mediated repression of the Hedgehog signaling pathway. The findings of the present study provided comprehensive evidence for the inhibition of OSC properties and chemoresistance by 17-AAG through repression of the GSK3β/Hedgehog signaling pathway, suggesting that 17-AAG may be a promising therapeutic agent for targeting OSCs.