4.8 Article

Absence of CD9 enhances adhesion-dependent morphologic differentiation, survival, and matrix metalloproteinase-2 production in small cell lung cancer cells

Journal

CANCER RESEARCH
Volume 66, Issue 19, Pages 9557-9565

Publisher

AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-06-1131

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While adhering to extracellular matrix proteins in vitro and in vivo, small cell lung cancer (SCLC) cells frequently show morphologic differentiation and are protected from apoptosis. Integrin beta(1)-mediated protein phosphorylation is suggested to be an essential signaling event in these processes. CD9 is an almost ubiquitously expressed tetraspanin protein that suppresses tumor progression by regulating cell motility and signaling through complex formation with, integrins. We reported previously that, among tetraspanins, CD9 is selectively absent in most SCLC cells and that ectopic expression of CD9 suppresses their motility. Here, we show that the ectopic expression of CD9 suppressed neurite-like process outgrowth and promoted apoptotic death of SCLC cells that were adherent to fibronectin in serum-starved conditions. This correlated with attenuation of adhesion-dependent phosphorylation of Akt but not that of focal adhesion kinase or c-Jun NH2-terminal kinase. Treatment of CD9(-) parent cells with a phosphatidylinositol 3-kinase (PI3K) inhibitor, LY294002, inhibited process outgrowth and survival, suggesting that PI3K/Akt signaling is required for the morphologic change-and cell survival. Production of matrix metalloproteinase (MMP)-2 was likewise suppressed in the CD9 transfectants and in LY294002-treated parent cells. These results suggest that the absence of CD9 in SCLC cells may contribute to postadhesive morphologic differentiation, survival, and MMP-2 production via PI3K/Akt pathway.

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