Abstract
Smac mimetic compounds (SMC) are novel small molecules being developed for cancer therapy. The mechanism of SMC-induced sensitivity in cancer cells depends on autocrine release of tumor necrosis factor alpha (TNFalpha); however, potential mechanisms of resistance remain unknown. Here, we investigated the molecular profile and cytotoxic responsiveness of a diverse panel of 51 cancer cell lines to combinations of a dimeric SMC (AEG40730), death ligand TNFalpha, and tumor necrosis factor-related apoptosis-inducing ligand. Synergy was seen in combination with death receptor agonists in some cells, although single-agent activity was limited to a fewsensitive lines. Unexpectedly, the majority of cell lines resistant to combinations of SMC-AEG40730 and death ligands expressed caspase-8, FADD, RIP1, and ligand receptors necessary for apoptosis execution. Furthermore, TNFalpha-mediated ubiquitination of RIP1 was repressed by SMC-AEG40730 treatment, leading to the formation of the proapoptosis complex II. However, in resistant cancer cells, SMC-AEG40730 repressed TNFalpha-mediated c-jun-NH(2)-kinase activation and the levels of caspase-8 inhibitor c-FLIP were persistently elevated, in contrast to SMC-responsive cancer cells. Importantly, the silencing of c-FLIP restored SMC sensitivity in previously resistant cancer cells by allowing ligand-mediated activation of caspase-8 and caspase-3 to proceed. Together, these results provide mechanistic insight into the action of SMCs, demonstrating that the deciphering of the relevant molecular signature in cancer cells leads to the prediction of cancer cell responsiveness to SMC treatment. Furthermore, a majority of resistant cancer cells were sensitized to SMC-AEG40730 and TNFalpha by down-regulating c-FLIP, suggesting novel approaches in the use of SMCs and c-FLIP antagonists in treating cancer.
Highlights
Smac mimetic compounds (SMC) are a class of small-molecule therapeutics currently in clinical trials for cancer [1]
Given that we found in resistant cancer cells that SMCAEG40730 has the ability to knock down cIAPs, but that reduced ubiquitination of RIP1 still occurs (Fig. 2A and data not shown), we further examined the effect of SMC on TNFa-mediated classic NFnB pathway
The presence of TNFa or tumor necrosis factorrelated apoptosis-inducing ligand (TRAIL) enhances the ability of SMC to induce apoptosis, many cancer cell lines remain resistant or only modestly responsive to SMC treatment for unknown reasons
Summary
Smac mimetic compounds (SMC) are a class of small-molecule therapeutics currently in clinical trials for cancer [1]. The targets of SMC are the inhibitor of apoptosis (IAP) proteins that include cIAP1, cIAP2, and XIAP, all of which possess three baculoviral IAP repeat (BIR) domains and a ubiquitin E3 ligase RING domain. The absence of cIAPs facilitates the recruitment of RIP1 to the tumor necrosis factor receptor 1 (TNF-R1), promoting the activation of the classic NF-nB pathway [4]. The induction of these NF-nB pathways leads to TNFa production. With cIAPs depleted, TNFa cannot promote RIP1 ubiquitination [3, 10, 11], and, as a consequence, RIP1 is released from the TNF-R1 complex. The death-inducing complex II containing RIP1, FADD, and caspase-8 is formed, activating the extrinsic apoptotic pathway [12]
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