Fas is a member of the TNF death receptor superfamily. Despite other “non-apoptotic” cellular responses emanating from its signaling, the major and best known function of Fas is apoptosis. To avoid apoptosis, cancer cells, including breast cancer cells, tend to down-regulate Fas expression or alter the expression of key mediators of the Fas-mediated apoptosis signaling pathway to advance the disease. Therefore, therapeutic intervention of tumor cell resistance to Fas-mediated apoptosis potentially represents an effective approach to render tumor cell sensitivity to FasL+ cytotoxic T lymphocytes (CTL) of the host immunosurveillance system or to CTL-based adoptive cancer immunotherapy to suppress tumor progression. We report here that sublethal doses of ceramide analog LCL85 effectively overcome metastatic human breast cancer cells to FasL-induced apoptosis in vitro. Although it has been shown that ceramide targets the Bcl-2 family proteins to induce tumor cell apoptosis, we observed that LCL85 does not alter Bak, Bax, Bcl-2 and Bcl-xL protein levels in metastatic human breast cancer cells. Instead, we determined that LCL85 dramatically decreased cIAP1 and xIAP protein levels in the metastatic human breast cancer cells. Consistent with its apoptosis sensitization activity, subtoxic doses of LCL85 suppressed primary breast cancer growth. More importantly, subtoxic doses of LCL85 effectively suppressed spontaneous lung metastasis in an orthotopic breast cancer mouse model. Furthermore, LCL85 exhibited no significant liver toxicity in vivo at the effective doses. Our data thus suggest that LCL85, although effective as a single agent in suppression of tumor development at high doses, might be more valuable if used at a sublethal dose as a sensitizer for enhancing the efficacy of FasL-based cancer therapy, particularly CTL-based cancer immunotherapy.

Note: This abstract was not presented at the meeting.

Citation Format: Xia Li, Amy V. Paschall, Aiping Bai, Jacek Bielawski, Alicja Bielawska, Kebin Liu. Ceramide analog sensitizes breast cancer cells to Fas-mediated apoptosis to suppress spontaneous lung metastasis. [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 2772. doi:10.1158/1538-7445.AM2014-2772