Hsp90 Is a Novel Target Molecule of CDDO-Me in Inhibiting Proliferation of Ovarian Cancer Cells

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.

HDAC and Ku70 axis- an effective target for apoptosis induction by a new 2-cyano-3-oxo-1,9-dien glycyrrhetinic acid analogue

“…4B ) and decreases the AKT level. It has been previously shown that CDDO-Me is a HSP90 inhibitor and inhibition of HSP90 by several agents causes Noxa induction 47 , 48 . Moreover, AKT is a client protein of HSP90 and the ability of HSP90 binding to client proteins is regulated by HDAC6.…”

Electrophile Modulation of Inflammation: A Two-Hit Approach

“…Interestingly, NRF2 activation by this compound occurred by way of a Cys 151 -independent mechanism while Cys 273 and Cys 288 accounted for nearly 50% of KEAP1-NO 2 -OA interactions [56]. In contrast, sulforaphane activates NRF2 most commonly through KEAP1 adduction at Cys 151 [57]. The antioxidant response gene products downstream of NRF2 may prevent oxidation of susceptible Cys or reverse this effect through the reduction of these same moieties.…”

“…Moreover, itaconate is believed to exert its anti-inflammatory effect in part through the activation of the EpRE/ARE. This metabolite activates antioxidant and anti-inflammatory effects through alkylation of Cys 151 , Cys 257 , Cys 273 , Cys 288 , and Cys 297 on the KEAP1 protein [111]. However, these studies were conducted with the use of the itaconate surrogate, octyl-itaconate and it has yet to be shown that endogenous levels of itaconate, which reach millimolar concentrations, are capable of PTM of KEAP1 in vivo.…”

“…CDDO-Me activation of the EpRE/ARE regulates the redox balance and, subsequently, the bioenergetic demands of the cells. In addition, CDDO-Me has demonstrated the ability to bind to the ATP-dependent molecular chaperon, HSP90 [ 151 ]. This interaction inhibits HSP90 clients, including elements of cell signaling cascades linked to cellular nutrient utilization such as EGFR, ErbB2, mTOR, and STAT3 [ 152 , 153 ].…”

Apoptotic and genomic effects of corilagin on SKOV3 ovarian cancer cell line

“…According to recent Globocan (2012) statistical data, 238,700 people were diagnosed as having epithelial ovarian cancer and there were 151,900 deaths worldwide 5. Despite various current surgical and therapeutic methods, the 5-year survival ratio of ovarian cancer is nearly 30%–40%, because of the absence of significant symptoms at earlier stages and late diagnosis at advanced or metastatic stages 6–10. In order to improve the overall survival ratio of patients with ovarian cancer, recent studies have targeted the finding of novel, effective, and nontoxic treatment strategies, as well as nutraceuticals, which are physiologically bioavailable and also cost-effective 11…”