Glioblastomas require integrin αvβ3/PAK4 signaling to escape senescence.
Glioblastomas require integrin αvβ3/PAK4 signaling to escape senescence.
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DOI：
10.1158/0008-5472.can-15-0988
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发表时间：
2015-11-01
期刊：
影响因子：
11.2
通讯作者：
Cheresh DA
中科院分区：
文献类型：
--
作者：
Franovic A;Elliott KC;Seguin L;Camargo MF;Weis SM;Cheresh DA
整合素αvβ3被认为是侵袭性和转移性疾病的驱动因素，并在胶质母细胞瘤进展期间上调。在这里，我们证明了整合素αvβ3允许胶质母细胞瘤细胞通过一种新的组织特异性效应机制来对抗衰老，该机制涉及细胞骨架调节激酶PAK 4的募集和激活。机制上，靶向αvβ3或PAK 4导致p21依赖性、p53非依赖性细胞衰老表型的出现。值得注意的是，胶质母细胞瘤细胞没有表现出对其他整合素或其他PAK家族成员的类似需求。此外，αvβ3/PAK 4依赖性在上皮癌中并不重要。总而言之，我们的研究结果证实，胶质母细胞瘤选择性地依赖于这一途径，作为逃避癌基因诱导的衰老的策略，这意味着抑制αvβ3/PAK 4信号传导轴可能为靶向这种侵袭性癌症提供新的治疗机会。
Integrin αvβ3 has been implicated as a driver of aggressive and metastatic disease, and is upregulated during glioblastoma progression. Here we demonstrate that integrin αvβ3 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 αvβ3 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, αvβ3/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 αvβ3/PAK4 signaling axis may offer novel therapeutic opportunities to target this aggressive cancer.