Sphingolipids are bioeffectors that mediate various cellular processes. We aimed to identify molecular targets of ceramide in the apoptosis pathway and to determine the efficacy of a ceramide analog in overcoming cancer cell resistance to apoptosis induction. We observed that exposure of human colon carcinoma cells to ceramide analog LCL85 results in apoptosis in a dose-dependent manner. Interestingly, a sublethal dose of LCL85 increased C16 ceramide content and overcame tumor cell resistance to FasL-induced apoptosis. Subsequently, treatment of tumor cells with exogenous C16 ceramide resulted in increased tumor cell sensitivity to FasL-induced apoptosis. LCL85 resembles Smac mimetic in sensitization of colon carcinoma cells to FasL-induced apoptosis by inducing proteasomal degradation of cIAP1 and xIAP proteins. Consistent with its apoptosis sensitization activity, LCL85 suppressed colon carcinoma cell metastatic potential in an experimental colon carcinoma lung metastasis mouse model. Taken together, we determined that a sublethal dose of LCL85 is effective as a sensitizer in overcoming apoptosis resistance of metastatic human colon carcinoma cells, and LCL85 is effective in suppressing tumor metastasis in vivo.
Citation Format: Amy Paschall, Mary Zimmerman, Christina Torres, Dafeng Yang, May Chen, Xia Li, Erhard Bieberich, Aiping Bai, Jacek Bielawski, Alicja Bielawska, Kebin Liu. Ceramide analog targets xIAP and cIAP1 to sensitize metastatic colon carcinoma cells to apoptosis induction to suppress tumor progression. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2756. doi:10.1158/1538-7445.AM2014-2756