Abstract
Akt survival signaling has emerged as a predictor of poor prognosis in tumors resistant to chemotherapy. Despite the firm correlation between enhanced Akt survival signaling in resistant tumor tissue, there is a poor understanding of the exact mechanisms which elicit this robust pathway activation. In the present study we sought to uncover the full pathway of Akt activation in response to chemotherapy in order to fully elucidate mechanisms and proteins involved in chemotherapy resistance. Using breast and ovarian cancer cells, immunoprecipitations revealed that the CD44 glycoprotein initiates a unique scaffolding effect with the Ezrin/Radixin/Moesin (ERM) proteins and Akt in response to the anti-tubulin chemotherapies, docetaxel and vincrisine. Knockdown of CD44 using siRNA revealed that the activation of Akt(ser473) and ERM(tyr353) by chemotherapy are abolished in a time and dose dependent manner. Flow cytometry, caspase activation and cell viability assays confirmed that loss of Akt signaling sensitizes cancer cells to chemotherapy-induced apoptosis and a similar sensitivity was observed in the absence of CD44 expression. Furthermore, immunoprecipitations revealed that inhibition of EGFR using the small molecule inhibitor, Erlotinib, prevented CD44/ERM/Akt scaffolding in response to chemotherapy. In summary, CD44 and ERM scaffolding is responsible for the activation of Akt survival signaling induced by chemotherapy, in-vitro. Loss of CD44 sensitizes cancer cells to apoptosis. This scaffolding effect is dependent on the activity of EGFR, suggesting that a unique interaction exists between this ErbB1 receptor tyrosine kinase and the CD44 glyco-protein. This is the first evidence for cell surface events which precipitate survival signaling in cancer cells as a consequence of chemotherapy. These findings elucidate novel biomarker interactions for translation in the clinical setting.
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 27. doi:1538-7445.AM2012-27
- ©2012 American Association for Cancer Research
Volume 72, Issue 8 Supplement
