ECM overrides DNA damage-induced cell cycle arrest and apoptosis in small-cell lung cancer cells through β1 integrin-dependent activation of PI3-kinase
ECM overrides DNA damage-induced cell cycle arrest and apoptosis in small-cell lung cancer cells through β1 integrin-dependent activation of PI3-kinase
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DOI：
10.1038/sj.cdd.4401849
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发表时间：
2006-10-01
影响因子：
12.4
通讯作者：
Sethi, T.
中科院分区：
文献类型：
--
作者：
Hodkinson, P. S.;Elliott, T.;Sethi, T.
化疗耐药的出现仍然是小细胞肺癌（SCLC）治疗中的主要问题。我们证明，细胞外基质（ECM）激活磷脂酰肌醇3-激酶（PI 3-激酶）信号在SCLC细胞，并阻止依托泊苷诱导的caspase-3激活和随后的细胞凋亡β 1整合素/PI 3激酶依赖性的方式。重要的是，我们发现依托泊苷和辐射诱导SCLC细胞凋亡前的G2/M期细胞周期阻滞，ECM通过覆盖p21（Cip 1/WAF 1）和p27（Kip 1）的上调和细胞周期蛋白E、A和B的下调来防止这种情况。这些作用通过PI 3-激酶信号传导的药理学和遗传学抑制而消除。重要的是，我们表明化学保护不是由改变的SCLC细胞增殖或DNA修复介导的。因此，ECM通过β 1整联蛋白介导的PI 3-激酶激活超越治疗诱导的细胞周期停滞和细胞凋亡，使SCLC细胞在持续DNA损伤的情况下存活，提供了一个模型来解释获得性耐药性的出现。
The emergence of resistance to chemotherapy remains a principle problem in the treatment of small-cell lung cancer (SCLC). We demonstrate that extracellular matrix (ECM) activates phosphatidyl inositol 3-kinase (PI3-kinase) signaling in SCLC cells and prevents etoposide-induced caspase-3 activation and subsequent apoptosis in a beta 1 integrin/PI3kinase- dependent manner. Crucially we show that etoposide and radiation induce G2/M cell cycle arrest in SCLC cells prior to apoptosis and that ECM prevents this by overriding the upregulation of p21(Cip1/WAF1) and p27(Kip1) and the down-regulation of cyclins E, A and B. These effects are abrogated by pharmacological and genetic inhibition of PI3- kinase signaling. Importantly we show that chemoprotection is not mediated by altered SCLC cell proliferation or DNA repair. Thus, ECM via beta 1 integrin-mediated PI3- kinase activation overrides treatment-induced cell cycle arrest and apoptosis, allowing SCLC cells to survive with persistent DNA damage, providing a model to account for the emergence of acquired drug resistance.