Journal
CELL DEATH AND DIFFERENTIATION
Volume 13, Issue 10, Pages 1776-1788Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.cdd.4401849
Keywords
cancer; extracellular matrix; cell cycle; apoptosis; chemoresistance
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Funding
- Medical Research Council [G9900991B, G84/6336] Funding Source: researchfish
- MRC [G84/6336] Funding Source: UKRI
- Medical Research Council [G84/6336] Funding Source: Medline
- Wellcome Trust Funding Source: Medline
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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.
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