Abstract
Synthetic triterpenoid methyl-2-cyano-3, 12-dioxooleana-1, 9(11)-dien-28-oate (CDDO-Me) has been shown as a promising agent against ovarian cancer. However, the underlying mechanism is not well understood. Here, we demonstrate that CDDO-Me directly interacts with Hsp90 in cells by cellular thermal shift assay. CDDO-Me treatment leads to upregulation of Hsp70 and degradation of Hsp90 clients (ErbB2 and Akt), indicating the inhibition of Hsp90 by CDDO-Me in cells. Knockdown of Hsp90 significantly inhibits cell proliferation and enhances the anti-proliferation effect of CDDO-Me in H08910 ovarian cancer cells. Dithiothreitol inhibits the interaction of CDDO-Me with Hsp90 in cells and abrogates CDDO-Me induced upregulation of Hsp70, degradation of Akt and cell proliferation inhibition. This suggests the anti-ovarian cancer effect of CDDO-Me is possibly mediated by the formation of Michael adducts between CDDO-Me and reactive nucleophiles on Hsp90. This study identifies Hsp90 as a novel target protein of CDDO-Me, and provides a novel insight into the mechanism of action of CDDO-Me in ovarian cancer cells.
Highlights
Ovarian cancer is one of the leading causes of cancer deaths from gynecological malignancy
We demonstrated that Heat shock protein 90 (Hsp90) is a novel target protein of CDDO-Me in ovarian cancer cells, which contributes to the anti-cancer effect of CDDO-Me in ovarian cancer cells
In order to know whether CDDO-Me interacts with Hsp90 in cells, Cellular Thermal Shift Assay (CETSA), a newly developed method to evaluate drug binding to target protein in cells, was performed
Summary
Ovarian cancer is one of the leading causes of cancer deaths from gynecological malignancy. Despite great advances in chemotherapy and surgical treatment, 70 to 90% of women with ovarian cancer will present a complete response after initial treatment and develop relapse within 2 years and the 5-year survival rate of patients with advanced ovarian cancer remains at approximately 30% [1]. In the USA, estimated 22, 000 new cases of ovarian cancer were predicted to be diagnosed in 2014 resulting in ~14, 000 deaths associated with this disease [2]. To improve outcomes for women with advanced ovarian cancer, significant efforts have been devoted to identify protein targeted agents [3].
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