HSP90 and the cancer transcriptome: a comprehensive review of inhibitors and mechanistic insights

This review summarizes the structure, function, expression, and inhibitors of HSP90, the chaperone, in cancers. It systematically investigates the effects of HSP90 inhibitors, including AUY922, B11B021, CCT-018159, D7-gedunin, geldanamycin, and gedunin, across a range of cancer cell lines (HCC151, HT29, MCF7, PC3, VCAP, and A375) and a normal HA1E cell line, using data from the CLUE database. Our analysis reveals that treatment with these HSP90 inhibitors induces significant stress responses in tumor cells, initiating intrinsic and extrinsic apoptotic pathways. The HSP90AA1, HSP90AB1, HSP27, HSP70, VEGF, and NOTCH exhibited notable upregulation at 24 h post-treatment compared to 6 h, indicating a time-dependent increase in cellular stress (heat shock response) and activation of pro-survival signaling mechanisms. Additionally, the study highlights a significant upregulation of immune-related pathways, including those involving IL10, IL3, and IL7, following HSP90 inhibition, indicating that these inhibitors not only directly affect tumor cell viability but also modulate the tumor microenvironment by enhancing immune cell activation and cytokine release. The elevated levels of IL10 point to a dual role, where immune suppression mechanisms are also at play, potentially facilitating immune evasion by the tumor. The findings suggest that HSP90 inhibitors exhibit varying mechanisms of action across different cancer cell lines despite the presence of some common targets. These insights highlight the need for further investigation into the precise mechanisms of HSP90 inhibitors to optimize their therapeutic potential in different cancers.