XIAP-targeting drugs re-sensitize PIK3CA-mutated colorectal cancer cells for death receptor-induced apoptosis.

M Ehrenschwender,S Bittner,H Wajant,K Seibold

doi:10.1038/cddis.2014.534

Abstract

Mutations in the oncogenic PIK3CA gene are found in 10–20% of colorectal cancers (CRCs) and are associated with poor prognosis. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and agonistic TRAIL death receptor antibodies emerged as promising anti-neoplastic therapeutics, but to date failed to prove their capability in the clinical setting as especially primary tumors exhibit high rates of TRAIL resistance. In our study, we investigated the molecular mechanisms underlying TRAIL resistance in CRC cells with a mutant PIK3CA (PIK3CA-mut) gene. We show that inhibition of the constitutively active phosphatidylinositol-3 kinase (PI3K)/Akt signaling pathway only partially overcame TRAIL resistance in PIK3CA-mut-protected HCT116 cells, although synergistic effects of TRAIL plus PI3K, Akt or cyclin-dependent kinase (CDK) inhibitors could be noted. In sharp contrast, TRAIL triggered full-blown cell death induction in HCT116 PIK3CA-mut cells treated with proteasome inhibitors such as bortezomib and MG132. At the molecular level, resistance of HCT116 PIK3CA-mut cells against TRAIL was reflected by impaired caspase-3 activation and we provide evidence for a crucial involvement of the E3-ligase X-linked inhibitor of apoptosis protein (XIAP) therein. Drugs interfering with the activity and/or the expression of XIAP, such as the second mitochondria-derived activator of caspase mimetic BV6 and mithramycin-A, completely restored TRAIL sensitivity in PIK3CA-mut-protected HCT116 cells independent of a functional mitochondrial cell death pathway. Importantly, proteasome inhibitors and XIAP-targeting agents also sensitized other CRC cell lines with mutated PIK3CA for TRAIL-induced cell death. Together, our data suggest that proteasome- or XIAP-targeting drugs offer a novel therapeutic approach to overcome TRAIL resistance in PIK3CA-mutated CRC.

Highlights

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) emerged as a promising anti-cancer agent, capable of selectively inducing cell death in tumor cells.[4]
We have recently found that mutant PIK3CA licensed TRAIL and CD95L to induce an amoeboid morphology in Colorectal cancer (CRC) cells, which is associated with increased invasiveness in vitro.[9]
Gene targeting of PIK3CA in the CRC cell line HCT116 revealed that exclusive expression of a PIK3CA allele harboring an activating H1047R substitution (HCT116 PIK3CA-mut) in exon 20 conferred resistance to TRAIL-induced apoptosis (Figure 1a).[9,10]

Summary

Introduction

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) emerged as a promising anti-cancer agent, capable of selectively inducing cell death in tumor cells.[4] TRAIL binding to TRAIL receptor 1 (TRAIL-R1) or TRAIL-R2 induces formation of a chain-like death-inducing signaling complex (DISC). This allows stepwise caspase-8 activation and initiates a cascade of proteolytic cleavage events activating caspase-3 and triggering the execution phase of apoptosis. High levels of IAPs or deregulated expression of Bcl[2] family proteins are common in human cancers and often confer apoptosis resistance This hampers efficacy of TRAIL-based therapies and to date, the therapeutic benefit of TRAIL in clinical trials is rather limited.[8]. Our results indicate that targeting XIAP or the proteasome in CRC with PIK3CA mutations may offer a promising strategy to exploit the therapeutic potential of TRAIL in cancer therapy

Methods

Results

Conclusion