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.