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Updated: Dec 6, 2025
Ex Vivo Treatment Response of Primary Tumors and/or Associated Metastases for Preclinical and Clinical Development of Therapeutics
Published on: October 2, 2014
Sulfoxythiocarbamate S-4 inhibits HSP90 in human cutaneous squamous cell carcinoma cells
Ying Zhang1, Garrett C VanHecke2, Young-Hoon Ahn2
1Jacqui Wood Cancer Centre, School of Medicine, University of Dundee, Scotland, UK.
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.
Insights
Sulfoxythiocarbamate S-4 inhibits heat shock protein 90 (HSP90) in cutaneous squamous cell carcinoma (cSCC) cells. This leads to apoptosis and cell cycle arrest, offering a promising strategy for cSCC treatment.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Cancer cells depend on molecular chaperones like heat shock protein 90 (HSP90).
- HSP90 inhibitors offer a potential therapeutic strategy for various cancers, especially those with high mutational burdens like cutaneous squamous cell carcinomas (cSCC).
Purpose of the Study:
- To investigate the mechanisms by which the HSP90 inhibitor S-4 affects the viability of human cSCC cells.
- To elucidate the downstream effects of S-4 on key cancer-related proteins and cellular processes.
Main Methods:
- Treatment of human cSCC cells with S-4.
- Analysis of HSP90 client protein levels (HER2, Bcl-2, cyclin D, CDK4).
- Assessment of apoptosis induction (cytochrome c release) and cell cycle progression (Rb phosphorylation, E2F release).
Main Results:
- S-4 effectively inhibits HSP90 in cSCC cells, leading to the depletion of oncoprotein HER2 and anti-apoptotic protein Bcl-2.
- Bcl-2 depletion triggers apoptosis via cytochrome c release from mitochondria.
- S-4 also depletes cyclin D and CDK4, inhibiting retinoblastoma protein phosphorylation and E2F release, thereby blocking G1-S cell cycle progression.
Conclusions:
- S-4 demonstrates comprehensive effectiveness against cSCC by inducing apoptosis and inhibiting cell division.
- These findings support the further development of S-4 and similar compounds for cancer prevention and treatment.
