Advertisement

Research Article Free access | 10.1172/JCI831

Activated Raf-1 causes growth arrest in human small cell lung cancer cells.

R K Ravi, E Weber, M McMahon, J R Williams, S Baylin, A Mal, M L Harter, L E Dillehay, P P Claudio, A Giordano, B D Nelkin, and M Mabry

The Oncology Center, The Johns Hopkins University Medical Institutions, Baltimore, Maryland 21287, USA.

Find articles by Ravi, R. in: JCI | PubMed | Google Scholar

The Oncology Center, The Johns Hopkins University Medical Institutions, Baltimore, Maryland 21287, USA.

Find articles by Weber, E. in: JCI | PubMed | Google Scholar

The Oncology Center, The Johns Hopkins University Medical Institutions, Baltimore, Maryland 21287, USA.

Find articles by McMahon, M. in: JCI | PubMed | Google Scholar

The Oncology Center, The Johns Hopkins University Medical Institutions, Baltimore, Maryland 21287, USA.

Find articles by Williams, J. in: JCI | PubMed | Google Scholar

The Oncology Center, The Johns Hopkins University Medical Institutions, Baltimore, Maryland 21287, USA.

Find articles by Baylin, S. in: JCI | PubMed | Google Scholar

The Oncology Center, The Johns Hopkins University Medical Institutions, Baltimore, Maryland 21287, USA.

Find articles by Mal, A. in: JCI | PubMed | Google Scholar

The Oncology Center, The Johns Hopkins University Medical Institutions, Baltimore, Maryland 21287, USA.

Find articles by Harter, M. in: JCI | PubMed | Google Scholar

The Oncology Center, The Johns Hopkins University Medical Institutions, Baltimore, Maryland 21287, USA.

Find articles by Dillehay, L. in: JCI | PubMed | Google Scholar

The Oncology Center, The Johns Hopkins University Medical Institutions, Baltimore, Maryland 21287, USA.

Find articles by Claudio, P. in: JCI | PubMed | Google Scholar

The Oncology Center, The Johns Hopkins University Medical Institutions, Baltimore, Maryland 21287, USA.

Find articles by Giordano, A. in: JCI | PubMed | Google Scholar

The Oncology Center, The Johns Hopkins University Medical Institutions, Baltimore, Maryland 21287, USA.

Find articles by Nelkin, B. in: JCI | PubMed | Google Scholar

The Oncology Center, The Johns Hopkins University Medical Institutions, Baltimore, Maryland 21287, USA.

Find articles by Mabry, M. in: JCI | PubMed | Google Scholar

Published January 1, 1998 - More info

Published in Volume 101, Issue 1 on January 1, 1998
J Clin Invest. 1998;101(1):153–159. https://doi.org/10.1172/JCI831.
© 1998 The American Society for Clinical Investigation
Published January 1, 1998 - Version history
View PDF
Abstract

Small cell lung cancer (SCLC) accounts for 25% of all lung cancers, and is almost uniformly fatal. Unlike other lung cancers, ras mutations have not been reported in SCLC, suggesting that activation of ras-associated signal transduction pathways such as the raf-MEK mitogen-activated protein kinases (MAPK) are associated with biological consequences that are unique from other cancers. The biological effects of raf activation in small cell lung cancer cells was determined by transfecting NCI-H209 or NCI-H510 SCLC cells with a gene encoding a fusion protein consisting of an oncogenic form of human Raf-1 and the hormone binding domain of the estrogen receptor (DeltaRaf-1:ER), which can be activated with estradiol. DeltaRaf-1:ER activation resulted in phosphorylation of MAPK. Activation of this pathway caused a dramatic loss of soft agar cloning ability, suppression of growth capacity, associated with cell accumulation in G1 and G2, and S phase depletion. Raf activation in these SCLC cells was accompanied by a marked induction of the cyclin-dependent kinase (cdk) inhibitor p27(kip1), and a decrease in cdk2 protein kinase activities. Each of these events can be inhibited by pretreatment with the MEK inhibitor PD098059. These data demonstrate that MAPK activation by DeltaRaf-1:ER can activate growth inhibitory pathways leading to cell cycle arrest. These data suggest that raf/MEK/ MAPK pathway activation, rather than inhibition, may be a therapeutic target in SCLC and other neuroendocrine tumors.

Version history
  • Version 1 (January 1, 1998): No description
Advertisement
Advertisement