Overcoming cancer cell resistance to Smac mimetic induced apoptosis by modulating cIAP-2 expression

Abstract

Smac mimetics target cancer cells in a TNFα-dependent manner, partly via proteasome degradation of cellular inhibitor of apoptosis 1 (cIAP1) and cIAP2. Degradation of cIAPs triggers the release of receptor interacting protein kinase (RIPK1) from TNF receptor I (TNFR1) to form a caspase-8 activating complex together with the adaptor protein Fas-associated death domain (FADD). We report here a means through which cancer cells mediate resistance to Smac mimetic/TNFα-induced apoptosis and corresponding strategies to overcome such resistance. These human cancer cell lines evades Smac mimetic-induced apoptosis by up-regulation of cIAP2, which although initially degraded, rebounds and is refractory to subsequent degradation. cIAP2 is induced by TNFα via NF-κB and modulation of the NF-κB signal renders otherwise resistant cells sensitive to Smac mimetics. In addition, other signaling pathways, including phosphatidyl inositol-3 kinase (PI3K), have the potential to concurrently regulate cIAP2. Using the PI3K inhibitor, LY294002, cIAP2 up-regulation was suppressed and resistance to Smac mimetics-induced apoptosis was also overcome.

USP11-dependent selective cIAP2 deubiquitylation and stabilization determine sensitivity to Smac mimetics

“…40,41 In addition to these observations, elevated cIAP2 expression in certain cell lines renders cells resistant to Smac mimetics, suggesting that cIAP2 is the decisive factor for protecting cancer cells from Smac mimetic-induced apoptosis. 22 In this study, we show that a USP11-dependent mechanism selectively and specifically regulates cIAP2 stability independent of cIAP1, which may explain the diverse responses of cancer cells to treatment with Smac mimetics, which are currently being tested in the clinic (Figure 7i). 5,14 In contrast to cIAP1, the cIAP2 degradation rate upon Smac mimetic treatment largely varied between cell lines and correlated with USP11 expression.…”

“…It has previously been reported that several Smac mimetics can induce cIAP2 expression in certain conditions. 22,33 To test whether BV6 increased cIAP2 expression in our conditions, we stimulated cells with TNFα in the presence or absence of BV6. cIAP2 induction following TNFα treatment was not affected by BV6 treatment, excluding the possibility of BV6 affecting cIAP2 transcriptional levels ( Figure 1d).…”

“…20,21 For example, cIAP2 upregulation via phosphoinositide 3-kinase (PI3K) upon compound 3 treatment in certain cell lines was shown to facilitate apoptosis evasion. 22 In addition, treatment with compounds A and C led to cIAP1 dimerization, without cIAP2 dimerization, resulting in the autoubiquitylation and subsequent degradation of cIAP1. These findings may explain why cIAP1 is degraded more efficiently than cIAP2 upon treatment with Smac mimetics.…”

IAPs: Guardians of RIPK1

“…NF-kB-mediated cIAP2 gene expression can provide protection against the lethal effects of TNF, presumably by targeting RIPK1 and NIK for ubiquitylation. 65,66 Surprisingly, cIAP2 that is upregulated in response to SMs is resistant to SM-mediated degradation. This is because SM-mediated degradation of cIAP2 depends on the presence of cIAP1.…”

Caspase-3 deficiency reveals a physiologic role for Smac/DIABLO in regulating programmed cell death

“…This is in contrast to findings reported using Smac mimetics, suggesting that such agents may overwhelm/ override normal necroptotic response in TNF-a/Fas-treated cells through interactions with cIAPs. [30][31][32] IAP-mediated inhibition of caspases appears insufficient to alter the nature or extent of PCD once initiated. What then is the purpose of such a system in vivo?…”