How invasive and metastatic tumor cells evade from anoikis induction remains unclear. We found that knockdown of RSK2 sensitizes diverse cancer cells to anoikis induction, which is mediated through phosphorylation targets, including apoptosis signal-regulating kinase 1 (ASK1) and cAMP response element-binding (CREB). We provide evidence to show that RSK2 inhibits ASK1 by phosphorylating S83, T1109 and T1326 through novel mechanism in which phospho-T1109/T1326 inhibits ATP binding to ASK1, while phospho-S83 attenuates ASK1 substrate MKK6 binding. Moreover, RSK2-CREB signaling pathway provides anti-anoikis protection by regulating gene expression of protein effectors that are involved in cell death regulation, including anti-apoptotic protein tyrosine kinase 6 (PTK6) and pro-apoptotic inhibitor of growth protein 3 (ING3). PTK6 overexpression or ING3 knockdown in addition to ASK1 knockdown further rescued the increased sensitivity to anoikis induction in RSK2 knockdown cells. These data together suggest that RSK2 functions as a signal integrator to provide anti-anoikis protection to cancer cells in both transcription-independent and -dependent manners, in part by signaling through ASK1 and CREB, and contributes to cancer cell invasion and tumor metastasis.
Citation Format: Lingtao Jin, Dan Li, Jongseok Lee, Gina N. Alesi, Jun Fan, Hee-Bum Kang, Dongsheng Wang, Haian Fu, Jack Taunton, Titus J. Boggon, Meghan Tucker, Ting-Lei Gu, Zhuo G. Chen, Dong M. Shin, Fadlo R. Khuri, Sumin Kang. p90RSK2 coordinates pro-apoptotic and anti-apoptotic signaling pathways to protect cancer cells from anoikis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2925. doi:10.1158/1538-7445.AM2013-2925