Glioblastomas require integrin ?v?3/PAK4 signaling to escape senescence.

ABSTRACT: Integrin ?v?3 has been implicated as a driver of aggressive and metastatic disease, and is upregulated during glioblastoma progression. Here, we demonstrate that integrin ?v?3 allows glioblastoma cells to counteract senescence through a novel tissue-specific effector mechanism involving recruitment and activation of the cytoskeletal regulatory kinase PAK4. Mechanistically, targeting either ?v?3 or PAK4 led to emergence of a p21-dependent, p53-independent cell senescence phenotype. Notably, glioblastoma cells did not exhibit a similar requirement for either other integrins or additional PAK family members. Moreover, ?v?3/PAK4 dependence was not found to be critical in epithelial cancers. Taken together, our findings established that glioblastomas are selectively addicted to this pathway as a strategy to evade oncogene-induced senescence, with implications that inhibiting the ?v?3-PAK4 signaling axis may offer novel therapeutic opportunities to target this aggressive cancer.

SUBMITTER: Franovic A 

PROVIDER: S-EPMC4631634 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature