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Oncogenic mutations in intestinal adenomas regulate Bim-mediated apoptosis induced by TGF-?.

ABSTRACT: In the majority of microsatellite-stable colorectal cancers (CRCs), an initiating mutation occurs in the adenomatous polyposis coli (APC) or ?-catenin gene, activating the ?-catenin/TCF pathway. The progression of resulting adenomas is associated with oncogenic activation of KRas and inactivation of the p53 and TGF-?/Smad functions. Most established CRC cell lines contain mutations in the TGF-?/Smad pathway, but little is known about the function of TGF-? in the early phases of intestinal tumorigenesis. We used mouse and human ex vivo 3D intestinal organoid cultures and in vivo mouse models to study the effect of TGF-? on the Lgr5(+) intestinal stem cells and their progeny in intestinal adenomas. We found that the TGF-?-induced apoptosis in Apc-mutant organoids, including the Lgr5(+) stem cells, was mediated by up-regulation of the BH3-only proapoptotic protein Bcl-2-like protein 11 (Bim). BH3-mimetic compounds recapitulated the effect of Bim not only in the adenomas but also in human CRC organoids that had lost responsiveness to TGF-?-induced apoptosis. However, wild-type intestinal crypts were markedly less sensitive to TGF-? than Apc-mutant adenomas, whereas the KRas oncogene increased resistance to TGF-? via the activation of the Erk1/2 kinase pathway, leading to Bim down-regulation. Our studies identify Bim as a critical mediator of TGF-?-induced apoptosis in intestinal adenomas and show that the common progression mutations modify Bim levels and sensitivity to TGF-? during intestinal adenoma development.

SUBMITTER: Wiener Z

PROVIDER: S-EPMC4040601 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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Oncogenic mutations in intestinal adenomas regulate Bim-mediated apoptosis induced by TGF-β.

Wiener Zoltán Z Band Arja M AM Kallio Pauliina P Högström Jenny J Hyvönen Ville V Kaijalainen Seppo S Ritvos Olli O Haglund Caj C Kruuna Olli O Robine Sylvie S Louvard Daniel D Ben-Neriah Yinon Y Alitalo Kari K

Proceedings of the National Academy of Sciences of the United States of America 20140513 21

In the majority of microsatellite-stable colorectal cancers (CRCs), an initiating mutation occurs in the adenomatous polyposis coli (APC) or β-catenin gene, activating the β-catenin/TCF pathway. The progression of resulting adenomas is associated with oncogenic activation of KRas and inactivation of the p53 and TGF-β/Smad functions. Most established CRC cell lines contain mutations in the TGF-β/Smad pathway, but little is known about the function of TGF-β in the early phases of intestinal tumori ...[more]

PMID: 24825889

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Project description:BackgroundEpidermal growth factor receptor (EGFR) mutations are present in the majority of patients with non-small cell lung cancer (NSCLC) responsive to the EGFR tyrosine kinase inhibitors (TKIs) gefitinib or erlotinib. These EGFR-dependent tumors eventually become TKI resistant, and the common secondary T790M mutation accounts for half the tumors with acquired resistance to gefitinib. However, the key proapoptotic proteins involved in TKI-induced cell death and other secondary mutations involved in resistance remain unclear. The objective of this study was to identify the mechanism of EGFR TKI-induced apoptosis and secondary resistant mutations that affect this process.Methods and findingsTo study TKI-induced cell death and mechanisms of resistance, we used lung cancer cell lines (with or without EGFR mutations), Ba/F3 cells stably transfected with EGFR mutation constructs, and tumor samples from a gefitinib-resistant patient. Here we show that up-regulation of the BH3-only polypeptide BIM (also known as BCL2-like 11) correlated with gefitinib-induced apoptosis in gefitinib-sensitive EGFR-mutant lung cancer cells. The T790M mutation blocked gefitinib-induced up-regulation of BIM and apoptosis. This blockade was overcome by the irreversible TKI CL-387,785. Knockdown of BIM by small interfering RNA was able to attenuate apoptosis induced by EGFR TKIs. Furthermore, from a gefitinib-resistant patient carrying the activating L858R mutation, we identified a novel secondary resistant mutation, L747S in cis to the activating mutation, which attenuated the up-regulation of BIM and reduced apoptosis.ConclusionsOur results provide evidence that BIM is involved in TKI-induced apoptosis in sensitive EGFR-mutant cells and that both attenuation of the up-regulation of BIM and resistance to gefitinib-induced apoptosis are seen in models that contain the common EGFR T790M and the novel L747S secondary resistance mutations. These findings also suggest that induction of BIM may have a role in the treatment of TKI-resistant tumors.

Dataset Information

Oncogenic mutations in intestinal adenomas regulate Bim-mediated apoptosis induced by TGF-?.

Publications

Oncogenic mutations in intestinal adenomas regulate Bim-mediated apoptosis induced by TGF-β.

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