Abstract 2581: Curcubitacin B exhibits cytotoxic effects by inhibiting ILK-Paxillin signaling in breast cancer cells

Abstract

Abstract Integrins are known to play an important role in promotion of cell motility and survival though activation of Integrin-Linked Kinase (ILK) signaling. Therefore ILK has been an attractive target to inhibit metastasis and tumor growth. Curcubitacin B (CuB) is a steroidal class of chemical present in the plants belonging to cucurbitaceae family. CuB has shown cytotoxic potential in several cancers by causing G2/M cell cycle arrest and inhibition of JAK/STAT3 pathway. However, the exact mechanism of CuB and its role in metastasis is not known. Integrins transmit cell survival signals through ILK-Paxillin complex and further play role in activating AKT signaling. This cascade ultimately works through the activation of Rho kinases like ROCK1 and RhoA. Our results show that CuB significantly suppressed the growth of MDA-MB-231 and MCF-7 breast cancer cells in a concentration and time-dependent manner. CuB also induced apoptosis and down-regulated ILK1 expression. In addition, CuB suppressed the phosphorylation of AKT at Ser473, paxillin at Tyr118 and down-regulated ROCK1 protein expression. Previous studies have shown that heregulin, a ligand of HER2 induces paxillin expression, indicating a correlation between HER2 and paxillin. Interestingly we observed significant downregulation of paxillin in HER2 overexpressing breast cancer cells, suggesting that CuB is equally effective in HER2 overexpressing tumor cells. Taken together our results indicate the anti-cancer effects of CuB in breast cancer cells by targeting paxillin, ILK and ROCK. Further detailed mechanistic work is in progress. [Supported in part by R01 grants CA106953 and CA129038 (to S.K.S) awarded by the National Cancer Institute]. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2581. doi:1538-7445.AM2012-2581