A novel antagonist to the inhibitors of apoptosis (IAPs) potentiates cell death in EGFR-overexpressing non-small-cell lung cancer cells

Abstract

In the effort to develop an efficient chemotherapy drug for the treatment of non-small-cell lung cancer (NSCLC), we analyzed the anti-tumorigenic effects of a novel small molecule targeting the inhibitor of apoptosis (IAPs), HM90822B, on NSCLC cells. HM90822B efficiently decreased IAP expression, especially that of XIAP and survivin, in several NSCLC cells. Interestingly, cells overexpressing epidermal growth factor receptor (EGFR) due to the mutations were more sensitive to HM90822B, undergoing cell cycle arrest and apoptosis when treated. In xenograft experiments, inoculated EGFR-overexpressing NSCLC cells showed tumor regression when treated with the inhibitor, demonstrating the chemotherapeutic potential of this agent. Mechanistically, decreased levels of EGFR, Akt and phospho-MAPKs were observed in inhibitor-treated PC-9 cells on phosphorylation array and western blotting analysis, indicating that the reagent inhibited cell growth by preventing critical cell survival signaling pathways. In addition, gene-specific knockdown studies against XIAP and/or EGFR further uncovered the involvement of Akt and MAPK pathways in HM90822B-mediated downregulation of NSCLC cell growth. Together, these results support that HM90822B is a promising candidate to be developed as lung tumor chemotherapeutics by targeting oncogenic activities of IAP together with inhibiting cell survival signaling pathways.

Differential Impacts of Alternative Splicing Networks on Apoptosis

“…Several reports indicated that ubiquitous expression of the survivin protein in most malignant cells, but not well-differentiated cells, functions as an inhibitor of the apoptosis protein (IAP, [48]). The survivin gene produces three alternatively spliced variants, including full length, delta Ex3 (∆Ex3), and 2B transcripts (Figure 4, [49]), which exhibit differential effects on the apoptotic process [50].…”

XIAP BIR domain suppresses miR-200a expression and subsequently promotes EGFR protein translation and anchorage-independent growth of bladder cancer cell

“…Although recent studies show the co-overexpression of XIAP and EGFR in many cancers [14, 35, 51, 52], and the high sensitive to anti-IAPs therapy if the cancers with EGFR overexpression [35], a possible association of XIAP with EGFR overexpression has never been explored in previous studies. We demonstrate here that XIAP is a strong positive regulator of EGFR expression in human bladder cancers and that XIAP BIR domain plays an important role in the mediation of EGFR protein expression by promoting its protein translation.…”

“…EGFR is overexpressed in basal-like muscle-invasive bladder cancers, which is sensitive to anti-EGFR therapy [25]. Other studies have shown that EGFR overexpressed tumors are more sensitive to anti-IAPs therapy [35] and XIAP also can lead to the resistance to anti-EGFR therapy [60]. Our studies here found that the overexpression of EGFR was attributed to BIR domain of abnormally expressed XIAP in bladder cancers (BCs), which offers an exciting new opportunity for us to explore the potential usage of XIAP BIR domain as a therapeutic target for invasive BCs, which may avoid the issue of XIAP related anti-EGFR therapy resistance, therefore in turn helping to improve the clinical outcome of patients with invasive BCs.…”

“…A recent study shows that tumor cells overexpressing EGFR are more sensitive to anti-IAPs therapy [35], suggesting a potential relationship between XIAP and EGFR in cancer cells. However, whether and how XIAP modulates EGFR expression remains largely unknown.…”

Expression of Survivin in Squamous Cell Lung Cancer and Its Correlation with Prognosis

“…There are recent notable studies evaluating the relationship between especially response to chemotherapy, EGFR resistance and surviving. [15][16][17][18] In this study, the relationship between survivin in both tumor and metastatic lymph nodes and clinicopathological parameters and survival in patients with squamous cell non-small cell lung cancer, which is more frequently seen in our country were evaluated. The study was approved by the Ethics Committee of Pamukkale University and scientific investigation project.…”