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Pharmacologic inhibition of RAF-->MEK-->ERK signaling elicits pancreatic cancer cell cycle arrest through induced expression of p27Kip1.
Cancer Res. 2005 Jun 01; 65(11):4870-80.CR

Abstract

Expression of mutationally activated RAS is a feature common to the vast majority of human pancreatic adenocarcinomas. RAS elicits its effects through numerous signaling pathways including the RAF-->mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinase [MEK]-->ERK MAP kinase pathway. To assess the role of this pathway in regulating cell proliferation, we tested the effects of pharmacologic inhibition of MEK on human pancreatic cancer cell lines. In eight cell lines tested, MEK inhibition led to a cessation of cell proliferation accompanied by G0-G1 cell cycle arrest. Concomitant with cell cycle arrest, we observed induced expression of p27Kip1, inhibition of cyclin/cyclin-dependent kinase 2 (cdk2) activity, accumulation of hypophosphorylated pRb, and inhibition of E2F activity. Using both antisense and RNA interference techniques, we assessed the role of p27Kip1 in the observed effects of MEK inhibition on pancreatic cancer cell proliferation. Inhibition of p27Kip1 expression in Mia PaCa-2 cells restored the activity of cyclin/cdk2, phosphorylation of pRb, and E2F activity and partially relieved the effects of U0126 on pancreatic cancer cell cycle arrest. Consistent with the effects of p27Kip1 on cyclin/cdk2 activity, inhibition of CDK2 expression by RNA interference also led to G0-G1 cell cycle arrest. These data suggest that the expression of p27Kip1 is downstream of the RAF-->MEK-->ERK pathway and that the regulated expression of this protein plays an important role in promoting the proliferation of pancreatic cancer cells. Moreover, these data suggest that pharmacologic inhibition of the RAF-->MEK-->ERK signaling pathway alone might tend to have a cytostatic, as opposed to a cytotoxic, effect on pancreatic cancer cells.

Authors+Show Affiliations

Cancer Research Institute and Department of Cellular and Molecular Pharmacology, University of California, San Francisco Comprehensive Cancer Center, San Francisco, California 94115, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15930308

Citation

Gysin, Stephan, et al. "Pharmacologic Inhibition of RAF-->MEK-->ERK Signaling Elicits Pancreatic Cancer Cell Cycle Arrest Through Induced Expression of P27Kip1." Cancer Research, vol. 65, no. 11, 2005, pp. 4870-80.
Gysin S, Lee SH, Dean NM, et al. Pharmacologic inhibition of RAF-->MEK-->ERK signaling elicits pancreatic cancer cell cycle arrest through induced expression of p27Kip1. Cancer Res. 2005;65(11):4870-80.
Gysin, S., Lee, S. H., Dean, N. M., & McMahon, M. (2005). Pharmacologic inhibition of RAF-->MEK-->ERK signaling elicits pancreatic cancer cell cycle arrest through induced expression of p27Kip1. Cancer Research, 65(11), 4870-80.
Gysin S, et al. Pharmacologic Inhibition of RAF-->MEK-->ERK Signaling Elicits Pancreatic Cancer Cell Cycle Arrest Through Induced Expression of P27Kip1. Cancer Res. 2005 Jun 1;65(11):4870-80. PubMed PMID: 15930308.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pharmacologic inhibition of RAF-->MEK-->ERK signaling elicits pancreatic cancer cell cycle arrest through induced expression of p27Kip1. AU - Gysin,Stephan, AU - Lee,Sang-Hyun, AU - Dean,Nicholas M, AU - McMahon,Martin, PY - 2005/6/3/pubmed PY - 2005/7/29/medline PY - 2005/6/3/entrez SP - 4870 EP - 80 JF - Cancer research JO - Cancer Res VL - 65 IS - 11 N2 - Expression of mutationally activated RAS is a feature common to the vast majority of human pancreatic adenocarcinomas. RAS elicits its effects through numerous signaling pathways including the RAF-->mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinase [MEK]-->ERK MAP kinase pathway. To assess the role of this pathway in regulating cell proliferation, we tested the effects of pharmacologic inhibition of MEK on human pancreatic cancer cell lines. In eight cell lines tested, MEK inhibition led to a cessation of cell proliferation accompanied by G0-G1 cell cycle arrest. Concomitant with cell cycle arrest, we observed induced expression of p27Kip1, inhibition of cyclin/cyclin-dependent kinase 2 (cdk2) activity, accumulation of hypophosphorylated pRb, and inhibition of E2F activity. Using both antisense and RNA interference techniques, we assessed the role of p27Kip1 in the observed effects of MEK inhibition on pancreatic cancer cell proliferation. Inhibition of p27Kip1 expression in Mia PaCa-2 cells restored the activity of cyclin/cdk2, phosphorylation of pRb, and E2F activity and partially relieved the effects of U0126 on pancreatic cancer cell cycle arrest. Consistent with the effects of p27Kip1 on cyclin/cdk2 activity, inhibition of CDK2 expression by RNA interference also led to G0-G1 cell cycle arrest. These data suggest that the expression of p27Kip1 is downstream of the RAF-->MEK-->ERK pathway and that the regulated expression of this protein plays an important role in promoting the proliferation of pancreatic cancer cells. Moreover, these data suggest that pharmacologic inhibition of the RAF-->MEK-->ERK signaling pathway alone might tend to have a cytostatic, as opposed to a cytotoxic, effect on pancreatic cancer cells. SN - 0008-5472 UR - https://www.unboundmedicine.com/medline/citation/15930308/Pharmacologic_inhibition_of_RAF__>MEK__>ERK_signaling_elicits_pancreatic_cancer_cell_cycle_arrest_through_induced_expression_of_p27Kip1_ L2 - http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=15930308 DB - PRIME DP - Unbound Medicine ER -