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Am. J. Respir. Cell Mol. Biol., Volume 20, Number 4, April, 1999 543-549

Raf-1 Causes Growth Suppression and Alteration of Neuroendocrine Markers in DMS53 Human Small-Cell Lung Cancer Cells

Rajani K. Ravi, Arunthathi Thiagalingam, Erich Weber, Martin McMahon, Barry D. Nelkin, and Mack Mabry

Oncology Center, Johns Hopkins University Medical Institutions, Baltimore, Maryland; and DNAX Research Institute of Molecular and Cellular Biology, Palo Alto, California

Ras mutations are common in lung adenocarcinomas and squamous-cell cancers, which are non-small-cell lung cancers (NSCLCs). However, small-cell lung cancers (SCLCs) rarely have ras mutations, suggesting that ras activation may not confer a growth advantage in these cells. In one SCLC cell line DMS53, activated ras expression induced increased neuroendocrine differentiation and decreased cell proliferation. We show here that DMS53 cells undergo differentiation and G1-specific growth arrest in response to ras/raf/ mitogen-activated protein kinase kinase (MEK)/mitogen-activated protein kinase (MAPK) pathway activation. To assess the consequences of activating the raf/MEK/MAPK pathway downstream of ras, we transfected a DMS53 cell line with Delta Raf-1:ER, an activatable form of c-raf-1. Delta Raf-1:ER activation suppressed cell proliferation and cloning on soft agar by 90% without evidence of apoptosis. Cell cycle analysis showed a reduced proportion of cells in S phase, and was associated with induction of the cyclin-dependent kinase (cdk) inhibitor p16INK4. Expression of the cell cycle-specific proteins pRb, Rb2/p130, p107, cyclin A, cdc-2, and E2F-1 was decreased after Delta Raf-1:ER activation in DMS53 cells. The activity cdk4 and cdk2 was also reduced, as consistent with cell cycle arrest in cells with activated Delta Raf-1:ER cells. In addition, Delta Raf-1:ER reduced the expression of neuroendocrine markers, gastrin releasing peptide, and ret gene in DMS53:Delta Raf-1:ER cells. These results provide further evidence that activation of the raf/MEK/ MAPK signaling pathway, which is associated with transformation in many circumstances, can reduce the growth of SCLC cells, and suggest that activation of this pathway might be clinically efficacious in some settings.




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