The presence of a constitutively active phosphoinositide 3-kinase in small cell lung cancer cells mediates anchorage-independent proliferation via a protein kinase B and p70s6k-dependent pathway.
Small cell lung cancer (SCLC) is characterized by early and widespread metastases. Anchorage-independent growth is pivotal to the ability of tumor cells to survive and metastasize in vivo and, under in vitro conditions, allows transformed cells to form colonies in semisolid medium. Here, we report that of five SCLC cell lines tested, all exhibited high basal constitutive phosphoinositide 3-kinase (PI 3-kinase) activity, which results in high basal protein kinase B (PKB) and ribosomal p70 S6 kinase activity (p70s6k). Inhibition of PI 3-kinase activity markedly inhibited SCLC cell proliferation in liquid culture as a result of stimulating apoptosis and promoting cell cycle delay in G1. Furthermore, PI 3-kinase inhibition reduced basal SCLC cell colony formation in agarose semisolid medium that could not be overcome by the addition of neuropeptide growth factors. Thus, constitutive PI 3-kinase activity in SCLC cells plays an important role in promoting the growth and anchorage independence of SCLC. This is not due to activating ras mutations or increased basal src or focal adhesion kinase activity. These data represent the first description of constitutively activated PI 3-kinase/PKB in any human cancer. Constitutive activation of these integrin-dependent signaling events provides a molecular explanation for the anchorage-independent growth of SCLC cells and may account for the nonadherent phenotype and highly metastatic nature of this aggressive cancer. Up-regulation of the PI 3-kinase/PKB pathway may, therefore, represent a novel target for therapeutic intervention in SCLC.
Moore
S M
SM
Rayne Laboratory, University of Edinburgh Medical School, Scotland, United Kingdom.
Rintoul
R C
RC
Walker
T R
TR
Chilvers
E R
ER
Haslett
C
C
Sethi
T
T
D000730:Androstadienes / Q000494:pharmacology; D018288:Carcinoma, Small Cell / Q000201:enzymology* / Q000473:pathology* / Q000556:secondary; D002448:Cell Adhesion; D002455:Cell Division; D002470:Cell Survival; D002867:Chromones / Q000494:pharmacology; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology* / Q000473:pathology*; D009025:Morpholines / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D019893:Ribosomal Protein S6 Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay; D015854:Up-Regulation; D000077191:Wortmannin
D000730:Androstadienes; D002867:Chromones; D009025:Morpholines; D009363:Neoplasm Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D019893:Ribosomal Protein S6 Kinases; D000077191:Wortmannin; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one