Susceptibility to cell death induced by blockade of MAPK pathway in human colorectal cancer cells carrying Ras mutations is dependent on p53 status

Constitutive activation of mitogen-activated protein kinase (MAPK) pathway is implicated in a variety of human malignancies especially those that carry Ras mutations and is currently exploited as a cancer therapeutic target. The variability of response by cancer cells to the inhibition of the Ras/MAPK pathway both in vivo and in vitro, however, suggests that the genetic background Of the tumor cell may modulate the effectiveness of this directed therapeutic. In a panel of colorectal cancer cell lines that carry Ras mutations and have constitutively active MEK/MAPK, we found that inhibition of the MAPK upstream kinase MEK by the small molecular MEK inhibitor U0126 induced cell death only in p53 wild-type cells. By contrast, p53-deficient cells were not affected by blocking the MEK/MAPK pathway. Using isogenic colon cancer cell lines and RNA interference, we show that loss of p53 significantly reduces MAPK phosphorylation and renders cells resistant to U0126 treatment. These findings reveal a critical role for p53 in MAPK-driven cell survival and place p53 upstream in the control cascade of MAPK activity. The therapeutic implication of these observations is that MAPK inhibitors will be most beneficial as a therapeutic agent in p53 normal colon cancers where constitutively active MAPK resulting from a Ras mutation is required for cell survival. (C) 2004 Elsevier Inc. All rights reserved.