Targeting inhibitors of apoptosis proteins suppresses medulloblastoma cell proliferation via G2/M phase arrest and attenuated neddylation of p21

Abstract

Medulloblastoma (MB) is the most common type of malignant childhood brain tumor. We previously showed that inhibitors of apoptosis proteins (IAP) small‐molecule inhibitors (LCL161 or LBW242) combined with chemotherapy have synergistic antiproliferative effects on MB cells. The synergistic antitumor effects of combination treatments happen through induction of autophagy and caspase‐3/7‐activated apoptosis. Here, we investigated the effects of IAP inhibitors or silencing IAP on cell cycle regulation. We discovered that treatment with IAP inhibitors or their combination with conventional chemotherapy (vincristine or cisplatin), as well as RNAi knockdown of cIAP1/2 or XIAP arrested MB cells in the G2/M phase through downregulation of cyclin B1‐CDK1 and cyclin A‐CDK1/2. Among these three IAPs, only silencing cIAP1 expression enhanced p21 dependent‐G2/M phase accumulation. IAP inhibitors reduced cIAP1 expression and increased p21 expression in time course experiments. Furthermore, cIAP1 can govern p21 proteasomal degradation via neddylation in lieu of ubiquitination. Inhibition of IAPs significantly abrogated cIAP1‐mediated p21 degradation. We also observed an inverse correlation between nuclear cIAP1 and nuclear p21 expressions in MB tumor tissues. These findings provide new mechanistic evidence of the influence of IAP inhibitors on MB cell proliferation through disruption of the cell cycle.

IAP and HDAC inhibitors interact synergistically in myeloma cells through noncanonical NF-κB– and caspase-8–dependent mechanisms

“…The impact of LCL/LBH exposure on proteins involved in the canonical NF-κB pathway was examined. Exposure (16 or 24 hr) of U266 or MM.1S to LCL (± LBH) markedly downregulated cIAP1 as previously described in multiple other cell types [19][20][21] but had a more modest effect on cIAP2 (Figure 2A and 2B, upper panels). Co-treatment also sharply induced γH2A.X, an indicator of DNA damage known to be induced by Smac-mimetics, 22 in both MM cell lines (Figure 2A and 2B, upper panels).…”

Bombyx mori Nucleopolyhedrovirus (BmNPV) Induces G2/M Arrest to Promote Viral Multiplication by Depleting BmCDK1

“…For example, IAPs disrupted chromosomal passenger complex (CPC) localization to the centromeres and interacted with the serine/threonine-protein kinase polo, indicating that iaps were involved in regulation of the cell cycle [52,53]. In medulloblastoma cells, ciap1/2 or xiap regulated G2/M phase progression via Cyclin B1-CDK1 and Cyclin A-CDK1/2 [71]. The treatment of human laryngeal carcinoma cells with Xiap-shRNA induced G0/G1 phase arrest [72].…”

Inhibition of BIRC2 Sensitizes α7-HPV-Related Cervical Squamous Cell Carcinoma to Chemotherapy

“…Clinical trials on patients with advanced solid tumors involving cotreatment with LCL161 and paclitaxel, as well as cotreatments with other chemotherapeutic agents, are ongoing [23,25]. Notably, studies have reported that a combination of LCL161 with cisplatin, vincristine, or immune checkpoint inhibitors produced the highest antitumor activity in cancer cells [26][27][28]. The combination of LCL161 with topotecan was tested for ovarian cancer [23]; however, this combination has yet to be tested for cervical cancer.…”