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Expression of the p53 target CDIP correlates with sensitivity to TNF?-induced apoptosis in cancer cells.

ABSTRACT: TNF? is a pleiotropic cytokine that signals for both survival and apoptotic cell fates. It is still unclear that the dual role of TNF? can be regulated in cancer cells. We previously described an apoptotic pathway involving p53?CDIP?TNF? that was activated in response to genotoxic stress. This pathway operated in the presence of JNK activation; therefore, we postulated that CDIP itself could sensitize cells to a TNF? apoptotic cell fate, survival, or death. We show that CDIP mediates sensitivity to TNF?-induced apoptosis and that cancer cells with endogenous CDIP expression are inherently sensitive to the growth-suppressive effects of TNF? in vitro and in vivo. Thus, CDIP expression correlates with sensitivity of cancer cells with TNF?, and CDIP seems to be a regulator of the p53-mediated death versus survival response of cells to TNF?. This CDIP-mediated sensitivity to TNF?-induced apoptosis favors pro- over antiapoptotic program in cancer cells, and CDIP may serve as a predictive biomarker for such sensitivity.

SUBMITTER: Brown-Endres L

PROVIDER: S-EPMC3349239 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Expression of the p53 target CDIP correlates with sensitivity to TNFα-induced apoptosis in cancer cells.

Brown-Endres Lauren L Schoenfeld David D Tian Fang F Kim Hyung-Gu HG Namba Takushi T Muñoz-Fontela César C Mandinova Anna A Aaronson Stuart A SA Lee Sam W SW

Cancer research 20120501 9

TNFα is a pleiotropic cytokine that signals for both survival and apoptotic cell fates. It is still unclear that the dual role of TNFα can be regulated in cancer cells. We previously described an apoptotic pathway involving p53→CDIP→TNFα that was activated in response to genotoxic stress. This pathway operated in the presence of JNK activation; therefore, we postulated that CDIP itself could sensitize cells to a TNFα apoptotic cell fate, survival, or death. We show that CDIP mediates sensitivity ...[more]

PMID: 22549949

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Project description:Members of the Inhibitor of APoptosis (IAP) protein family suppress apoptosis within tumor cells, particularly in the context of immune cell-mediated killing by the tumor necrosis factor (TNF) superfamily cytokines. Most IAPs are opposed endogenously by the second mitochondrial activator of caspases (SMAC), which binds to selected baculovirus IAP repeat (BIR) domains of IAPs to displace interacting proteins. The development of SMAC mimetics as novel anticancer drugs has gained impetus, with several agents now in human clinical trials. To further understand the cellular mechanisms of SMAC mimetics, we focused on IAP family members cIAP1 and cIAP2, which are recruited to TNF receptor complexes where they support cell survival through NF-?B activation while suppressing apoptosis by preventing caspase activation. We established fluorescence polarization (FP) assays for the BIR2 and BIR3 domains of human cIAP1 and cIAP2 using fluorochrome-conjugated SMAC peptides as ligands. A library of SMAC mimetics was profiled using the FP assays to provide a unique structure activity relationship (SAR) analysis compared to previous assessments of binding to XIAP. Potent compounds displayed mean inhibitory binding constants (Ki) of 9 to 27 nM against the BIR3 domains of cIAP1 and cIAP2, respectively. Selected compounds were then characterized using cytotoxicity assays in which a cytokine-resistant human tumor cell line was sensitized to either TNF or lymphotoxin-? (LT-?). Cytotoxicity correlated closely with cIAP1 and cIAP2 BIR3 binding activity with the most potent compounds able to reduce cell viability by 50%. Further testing demonstrated that active compounds also inhibit RIP1 binding to BIR3 of cIAP1 and cIAP2 in vitro and reduce steady-state cIAP1 protein levels in cells. Altogether, these data inform the SAR for our SMAC mimetics with respect to cIAP1 and cIAP2, suggesting that these IAP family members play an important role in tumor cell resistance to cytotoxicity mediated by TNF and LT-?.

Dataset Information

Expression of the p53 target CDIP correlates with sensitivity to TNF?-induced apoptosis in cancer cells.

Publications

Expression of the p53 target CDIP correlates with sensitivity to TNFα-induced apoptosis in cancer cells.

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