Carcinoma-associated fibroblasts (CAFs) promote tumor invasion by secreting soluble factors. A tagged triazine library was screened in our novel transwell coculture model of CAF and oral squamous cell carcinoma (OSCC). We discovered compound S06, which reduced OSCC invasion by inhibiting secretion of CAF-derived proinvasive chemokines. The N-terminus of Hsp90 was found to be the cellular target of S06. Importantly, S06 did not induce hepatic toxicity, a side effect associated with well-known Hsp90 inhibitors. Moreover, S06 inhibited tumor cell migration in a zebrafish xenograft model. Our results demonstrate that Hsp90 is a novel target for stromal-based therapy to modulate proinvasive molecular crosstalk within the tumor microenvironment. Furthermore, S06 represents a new class of Hsp90 inhibitor and is an attractive candidate for anticancer drug development.
Bibliographical noteFunding Information:
This research was supported by a grant from the National Research Foundation funded by the Korean government (MEST basic science research program NRF-2009-0067894 to D.-W.J.) and a grant from the Priority Research Centers Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2010-0029702 to J.K.). We also acknowledge the Bioimaging Research Center, Gwangju Institute of Science and Technology, for provision of microscopy facilities.
All Science Journal Classification (ASJC) codes
- Molecular Medicine
- Molecular Biology
- Drug Discovery
- Clinical Biochemistry