ECM overrides DNA damage-induced cell cycle arrest and apoptosis in small-cell lung cancer cells through beta1 integrin-dependent activation of PI3-kinase.
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 beta1 integrin/PI3-kinase-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 downregulation 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 beta1 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.
Hodkinson
P S
PS
MRC Centre for Inflammation Research, Queen's Institute of Medical Research, University of Edinburgh, 51 Little France Crescent, Edinburgh EH16 4SA, UK.
Elliott
T
T
Wong
W S
WS
Rintoul
R C
RC
Mackinnon
A C
AC
Haslett
C
C
Sethi
T
T
D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D018288:Carcinoma, Small Cell / Q000378:metabolism* / Q000473:pathology* / Q000628:therapy; D002448:Cell Adhesion; D002453:Cell Cycle; D045744:Cell Line, Tumor; D004249:DNA Damage; D005047:Etoposide / Q000494:pharmacology; D005109:Extracellular Matrix / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism*; D007797:Laminin / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology* / Q000628:therapy; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D014638:Vanadates / Q000494:pharmacology
D000970:Antineoplastic Agents; D019012:Integrin beta1; D007797:Laminin; D014638:Vanadates; D005047:Etoposide; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3