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[Cancer Research 60, 2104-2107, April 15, 2000]
© 2000 American Association for Cancer Research

Advances in Brief

U0126 Reverses Ki-ras-mediated Transformation by Blocking Both Mitogen-activated Protein Kinase and p70 S6 Kinase Pathways1

Hidesuke Fukazawa and Yoshimasa Uehara2

Department of Bioactive Molecules, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan

U0126, a recently introduced mitogen-activated protein kinase kinase (MAPK)/extracellular signal-regulated kinase kinase inhibitor reversed morphology and inhibited anchorage-independent growth of Ki-ras-transformed rat fibroblasts. Immunoblot analyses with phosphospecific antibodies indicated that in addition to MAPK, U0126 suppressed activation of p70S6K, but not Akt, at concentrations at which it normalized the transformed phenotypes. Another MAPK/extracellular signal-regulated kinase kinase inhibitor, PD98059, showed only marginal effects on p70S6K phosphorylation and did not effectively block Ki-ras-induced transformation. However, simultaneous inhibition of the MAPK pathway and the p70S6K pathway by PD98059 in conjunction with the p70S6K inhibitor rapamycin essentially restored the normal phenotype. U0126 or the combination of PD98059 and rapamycin flattened morphology of v-src-transformed cells, but did not reverse anchorage independence, although activation of both MAPK and p70S6K was blocked. The results suggest that normalization of Ki-ras-induced transformed phenotypes by U0126 is a consequence of concurrent inhibition of the MAPK and p70S6K pathways. Intervention of other pathway(s) appears to be required to completely antagonize transformation by v-src. Simultaneous blockade of more than one signal transduction pathway by combining selective inhibitors might be effective in suppressing uncontrolled tumorigenic growth.




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Copyright © 2000 by the American Association for Cancer Research.