ECM overrides DNA damage-induced cell cycle arrest and apoptosis in small-cell lung cancer cells through β1 integrin-dependent activation of PI3-kinase

被引：114

作者：

Hodkinson, P. S. ^{[1
]}

Elliott, T. ^{[1
]}

Wong, W. S. ^{[1
]}

Rintoul, R. C. ^{[1
]}

Mackinnon, A. C. ^{[1
]}

Haslett, C. ^{[1
]}

Sethi, T. ^{[1
]}

机构：

[1] Univ Edinburgh, Queens Inst Med Res, MRC, Ctr Inflammat Res, Edinburgh EH16 4SA, Midlothian, Scotland

来源：

CELL DEATH AND DIFFERENTIATION | 2006年 / 13卷 / 10期

基金：

英国惠康基金; 英国医学研究理事会;

关键词：

cancer; extracellular matrix; cell cycle; apoptosis; chemoresistance;

D O I：

10.1038/sj.cdd.4401849

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 [生物化学与分子生物学]; 081704 [应用化学];

摘要：

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.

引用

页码：1776 / 1788

页数：13

共 39 条

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Integrin signaling inhibits paclitaxel-induced apoptosis in breast cancer cells [J].