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BIM is the primary mediator of MYC-induced apoptosis in multiple solid tissues

ABSTRACT: C-MYC (henceforth MYC) is one of the most frequently overexpressed oncogenes in human cancer and even modestly deregulated MYC expression can initiate ectopic proliferation in many post-mitotic, terminally differentiated cell types in vivo. Metazoan organisms have consequently evolved a number of mechanisms to counteract MYC's oncogenic potential, of which apoptosis is arguably the best understood. However, the mechanisms through which MYC induces apoptosis remains controversial, with some studies implicating p19ARF-mediated stabilization of p53, followed by induction of pro-apoptotic BH3 family member NOXA and PUMA, while others argue for more direct regulation of BH3 proteins, especially BIM. The debate likely stems from the use of different experimental systems, modes of perturbation, and quite possibly different levels of MYC expression. Here, we use a single experimental system to systematically evaluate the roles of p19ARF and BIM during MYC-induced apoptosis, in vitro, in vivo, and in combination with a widely used tumoricidal chemotherapeutic, Doxorubicin. We find a common specific requirement for BIM during MYC-induced apoptosis in multiple settings, which does not extend to the p53-responsive BH3 family member PUMA, and find no evidence of a role for p19ARF during MYC-induced apoptosis in the tissues examined.

ORGANISM(S): Homo sapiens

PROVIDER: GSE59001 | GEO | 2015/05/18

SECONDARY ACCESSION(S): PRJNA254075

REPOSITORIES: GEO

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Project description:Translocation-related sarcomas (TRSs) harbor an oncogenic fusion gene generated by chromosome translocation and account for approximately one-third of all sarcomas; however, effective targeted therapies have not yet been established. We previously reported that a pan-PI3K inhibitor, ZSTK474, was suggested to be effective for sarcomas in a phase I clinical trial, and demonstrated its efficacy in preclinical model, particularly in cell lines from synovial sarcomas (SS), Ewing’s sarcomas (ES) and alveolar rhabdomyosarcomas (ARMS), all of which harbor chromosomal translocation. Actually, ZSTK474 selectively induced apoptosis in these types of sarcoma cell lines, but the precise mechanism of apoptosis induction remained unclear. Here, we performed transcriptional analyses in SS cell lines including Aska-SS, SYO-1, Yamato-SS and Fuji treated with or without ZSTK474. Gene set enrichment analyses (GSEA) and Gene ontology (GO) analysis revealed that SS cell lines treated with ZSTK474 significantly reduced signatures of PI3K signaling. In addition, upon treatment with ZSTK474, the expression of apoptosis and cell cycle related genes was significantly changed. Importantly, PI3K inhibitors triggered induction of PUMA and BIM, resulting in loss of mitochondrial membrane potential, and the expression knockdown of these genes by RNA interference efficiently suppressed the apoptosis, suggesting their functional involvement in the apoptosis progression. In contrast, TRS-derived cell lines/patient-derived cells from alveolar soft part sarcoma (ASPS), CIC-DUX4 sarcoma and dermatofibrosarcoma protuberans failed to undergo apoptosis nor induce PUMA and BIM expression, as well as cell lines derived from non-TRSs and carcinomas. These results indicate that PI3K inhibitors selectively induce apoptosis in selective TRSs such as ES and SS via the induction of PUMA and BIM and subsequent loss of mitochondrial membrane potential, which would be a proof of concept for PI3K-targeted therapy especially for such TRS patients.

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BIM is the primary mediator of MYC-induced apoptosis in multiple solid tissues

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