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 P70(S6K)-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 co nditions, allows transformed cells to form colonies in semisolid mediu m, Here, we report that of five SCLC cell lines tested, all exhibited high basal constitutive phosphoinositide 3-kinase (PI 3-kinase) activi ty, which results in high basal protein kinase B (PKB) and ribosomal p 70 S6 kinase activity (p70(s6k)). Inhibition of PI 3-kinase activity m arkedly inhibited SCLC cell proliferation in liquid culture as a resul t of stimulating apoptosis and promoting cell cycle delay in G(1), Fur thermore, PI 3-kinase inhibition reduced basal SCLC cell colony format ion in agarose semisolid medium that could not be overcome by the addi tion of neuropeptide growth factors, Thus, constitutive PI 3-kinase ac tivity in SCLC cells plays an important role in promoting the growth a nd anchorage independence of SCLC, This is not due to activating ras m utations or increased basal src or focal adhesion kinase activity. The se data represent the first description of constitutively activated PI 3-kinase/PKB in any human cancer. Constitutive activation of these in tegrin-dependent signaling events provides a molecular explanation for the anchorage-independent growth of SCLC cells and may account for th e nonadherent phenotype and highly metastatic nature of this aggressiv e cancer. Up-regulation of the PI 3-kinase/ PKB pathway may, therefore , represent a novel target for therapeutic intervention in SCLC.