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BRAF-induced tumorigenesis is IKKalpha dependent but NFκB independent

ABSTRACT: Tumor cells carrying KRAS mutations activate the NF-κB pathway by different mechanisms, which contribute to the acquisition of essential cancer properties. The BRAF kinase, a downstream mediator of KRAS, is also mutated in a subset of colorectal cancers (CRC), which predicts bad prognosis and therapy resistance. However, nothing is known on whether NF-κB participates of BRAF-mediated tumorigenesis. We here found that in CRC cells, mutant BRAF does not trigger canonical or alternative NF-κB signaling but induces p45-IKKα activation. Moreover, IKKα activity is required for BRAF-induced transformation and to support BRAF-dependent transcription in CRC cells. Activation of p45-IKKα downstream of BRAF requires the TAK1 kinase, and is associated to the endosomal compartment. Inhibition of endosomal V-ATPase abolished p45-IKKα phosphorylation, and induced apoptosis of BRAF mutated CRC cells. Pharmacologic inhibition of endosome acidification reduced the in vivo growth of tumors carrying mutant BRAF, and abrogated the metastatic capacity of a primary human CRC tumor with acquired resistance to standard chemotherapy in an orthotopic xenograft model.

ORGANISM(S): Homo sapiens

PROVIDER: GSE57979 | GEO | 2015/05/08

SECONDARY ACCESSION(S): PRJNA248640

REPOSITORIES: GEO

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BRAF-induced tumorigenesis is IKKalpha dependent but NF?B independent

Project description:Tumor cells carrying KRAS mutations activate the NF-?B pathway by different mechanisms, which contribute to the acquisition of essential cancer properties. The BRAF kinase, a downstream mediator of KRAS, is also mutated in a subset of colorectal cancers (CRC), which predicts bad prognosis and therapy resistance. However, nothing is known on whether NF-?B participates of BRAF-mediated tumorigenesis. We here found that in CRC cells, mutant BRAF does not trigger canonical or alternative NF-?B signaling but induces p45-IKK? activation. Moreover, IKK? activity is required for BRAF-induced transformation and to support BRAF-dependent transcription in CRC cells. Activation of p45-IKK? downstream of BRAF requires the TAK1 kinase, and is associated to the endosomal compartment. Inhibition of endosomal V-ATPase abolished p45-IKK? phosphorylation, and induced apoptosis of BRAF mutated CRC cells. Pharmacologic inhibition of endosome acidification reduced the in vivo growth of tumors carrying mutant BRAF, and abrogated the metastatic capacity of a primary human CRC tumor with acquired resistance to standard chemotherapy in an orthotopic xenograft model. 18 samples were analyzed: HT29 controls (n=3); HT28 BRAF inhibited (n=3), WiDr controls (n=3); WiDr BRAF inhibited (n=3); WiDr transduced with control shRNA (n=3) and WiDr transduced with shRNA against IKKalpha (n=3)

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