Direct Evidence for the Contribution of Activated N-ras and K-ras Oncogenes to Increased Intrinsic Radiation Resistance in Human Tumor Cell Lines

Eric J. Bernhard; Eric J. Stanbridge; Swati Gupta; Anjali K. Gupta; Daniel Soto; Vincent J. Bakanauskas; George J. Cerniglia; Ruth J. Muschel; W. Gillies McKenna

DOI: Published December 2000

Abstract

Transformation with ras oncogenes results in increased radiation survival in many but not all cells. In addition, prenyltransferase inhibitors, which inhibit ras proteins by blocking posttranslational modification, radiosensitize cells with oncogenic ras. These findings suggest that oncogenic ras contributes to intrinsic radiation resistance. However, because introduction of ras oncogenes does not increase radiation survival in all cells and because prenyltransferase inhibitors target molecules other than ras, these studies left the conclusion that ras increases the intrinsic radiation resistance of tumor cells in doubt. Here we show that genetic inactivation of K- or N-ras oncogenes in human tumor cells (DLD-1 and HT1080, respectively) leads to increased radiosensitivity. Reintroduction of the activated N-ras gene into the HT1080 line, having lost its mutant allele, resulted in increased radiation resistance. This study lends further support to the hypothesis that expression of activated ras can contribute to intrinsic radiation resistance in human tumor cells and extends this finding to the K- and N- members of the ras family. These findings support the development of strategies that target ras for inactivation in the treatment of cancer.

Footnotes

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
↵1 These studies were supported by NIH Grant CA75138 (to W. G. M., R. J. M., and E. J. B.) Grant CA73820 (to E. J. B.), and Grant CA69515 (to E. J. S.). Farnesyltransferase inhibitors were provided by Merck and Co., Inc.
↵2 To whom requests for reprints should be addressed, at Department of Radiation Oncology, 195 John Morgan Building, University of Pennsylvania, Philadelphia, PA 19104-6072. Phone: (215) 898-0078; Fax: (215) 898-0090; E-mail bernhard@mail.med.upenn.edu.