SNX-2112, an Hsp90 inhibitor, suppresses cervical cancer cells proliferation, migration, and invasion by inhibiting the Akt/mTOR signaling pathway

摘要

Patients with advanced-stage cervical cancer have a high rate of morbidity and mortality, predominantly due to the metastasis of cervical cancer cells. Therefore, the development of novel agents to prevent metastasis is required for improved cervical cancer therapeutics. SNX-2112, a potent and selective Hsp90 inhibitor, is an anticancer candidate in clinical trials for the treatment of some solid tumors and lymphomas. However, the effects of SNX-2112 on the migration and invasion of cervical cancer cells are unclear. This study aimed at exploring the effects of SNX-2112 on the migration and invasion of cervical cancer cells and revealing the underlying molecular mechanisms. We found that SNX-2112 significantly decreased the viability, colony formation ability, and migration of HeLa and U14 cells. The invasiveness of HeLa cells and the proteins involved in metastasis were markedly reduced after SNX-2112 treatment. SNX-2112 inactivated the focal adhesion kinase (FAK) and inhibited the expression levels of matrix metallopeptidase (MMP)-9, MMP-2, SLUG, SNAIL, beta-catenin, and Vimentin. Furthermore, SNX-2112 inhibited the protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway in HeLa cells by decreasing the phosphorylation of Akt, mTOR, S6, and eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1). It also reduced the expression levels of the endoplasmic reticulum (ER)-localized molecular chaperones, Calnexin and BiP, and unfolded protein response (UPR)-related proteins IRE1 alpha and PERK, suggesting that SNX-2112 can suppress ER stress and thus, inactivate the UPR in HeLa cells. Taken together, these findings indicate that SNX-2112 may efficiently suppress the proliferation, migration, and invasion of cervical cancer cells by inhibiting the Akt/mTOR pathway and could serve as a candidate drug for the treatment of human cervical cancer.