Abstract 2285: PKC activation sensitizes certain basal breast cancer cell lines to the Smac mimetic LBW242

Abstract

Abstract There is a need for novel strategies to initiate cancer cell death. One approach is the use of Smac mimetics, such as LBW242, which antagonize inhibitor of apoptosis proteins (IAP)s and facilitates cell death. Recent studies have shown that combinations of Smac mimetics and chemotherapeutic agents increase cancer cell death. Here we show that the protein kinase C (PKC) activator TPA together with LBW242 induce cell death in two basal breast cancer cell lines (MDA-MB-468 and BT549), that are resistant to LBW242 as a single agent. Eleven other LBW242-insensitive cancer cell lines were not influenced by the TPA+LBW242 combination. The TPA+LBW242 effect was suppressed by the PKC inhibitor GF109203X, indicating dependence on PKC enzymatic activity. The PKC effect was mediated via increased synthesis and release of TNFα which can induce death in the presence of LBW242. The cell death, coinciding with caspsae-3 cleavage, was suppressed by caspase inhibition and preceded by the association of RIP1 with Caspase-8, as seen in complex II mediated apoptosis. Our data suggest that in certain basal breast cancer cell lines co-treatment of TPA with LBW242 induces cell death highlighting the potential of using these pathways as molecular targets for basal-like breast cancers. Citation Format: Louise Cornmark, Christian Holmgren, Katarzyna Masoumi, Christer Larsson. PKC activation sensitizes certain basal breast cancer cell lines to the Smac mimetic LBW242. [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 2285. doi:10.1158/1538-7445.AM2014-2285