Abstract
Cancer cells rely heavily on molecular chaperones, such as heat shock protein 90 (HSP90), and their co-chaperones. The development of HSP90 inhibitors is an attractive therapeutic approach that has the potential to affect multiple hallmarks of cancer. Such approach is particularly needed for tumors that carry large mutational burdens, including cutaneous squamous cell carcinomas (cSCC). We previously identified sulfoxythiocarbamate S-4 as an HSP90 inhibitor. In this study, we investigated the mechanism(s) by which S-4 compromises the viability of human cSCC cells. S-4 inhibits HSP90 and causes depletion of its clients HER2, a tyrosine kinase oncoprotein, and Bcl-2, an anti-apoptotic protein. The decrease in Bcl-2 is accompanied by cytochrome c release from mitochondria into the cytoplasm, suggesting apoptosis. In the surviving cells, depletion of the HSP90 clients cyclin D and CDK4 by S-4 prevents phosphorylation of the retinoblastoma protein Rb and the release of transcription factor E2F, inhibiting G1-S cell cycle progression and cell division. These findings illustrate the comprehensive effectiveness of S-4 and encourage future development of compounds of this type for cancer prevention and treatment.