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Originally published In Press as doi:10.1074/jbc.M007154200 on August 30, 2000

J. Biol. Chem., Vol. 275, Issue 50, 39001-39011, December 15, 2000
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Oncogenic Ras Mediates Apoptosis in Response to Protein Kinase C Inhibition through the Generation of Reactive Oxygen Species*

James S. Liou, Chang-Yan Chen, James S. Chen, and Douglas V. FallerDagger

From the Boston University School of Medicine, Cancer Research Center, Boston, Massachusetts 02118

Ras is a well established modulator of apoptosis. Suppression of protein kinase C (PKC) activity can selectively induce apoptosis in cells expressing a constitutively activated Ras protein. We wished to determine whether reactive oxygen species serve as an effector of Ras-mediated apoptosis. Ras-transformed NIH/3T3 cells contained higher basal levels of intracellular H2O2 compared with normal NIH/3T3 cells, and PKC inhibition up-regulated ROS to 5-fold greater levels in Ras-transformed cells than in normal cells. Treatment with N-acetyl-L-cysteine reduced both the basal and inducible levels of intracellular H2O2 in NIH/3T3-Ras cells and antagonized the induction of apoptosis by PKC inhibition. Culturing NIH/3T3-Ras cells in low oxygen conditions, which prevents ROS generation, also inhibited the apoptotic response to PKC inhibition. These results suggest that reactive oxygen species are necessary as downstream effectors of the Ras-mediated apoptotic response to PKC inhibition. However, the generation of ROS alone is not sufficient to induce apoptosis in Ras-transformed cells because inhibition of cell cycle progression prevented the induction of apoptosis in NIH/3T3-Ras cells without inhibiting the generation of intracellular H2O2 observed after PKC inhibition. These findings suggest that continued cell cycle progression of Ras-transformed cells during PKC inhibition is also necessary for the induction of apoptosis.

* This work was supported in part by Research Grant 50459 from the NCI, National Institutes of Health (to D. V. F.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger To whom correspondence should be addressed: Cancer Research Center, Boston University School of Medicine, 715 Albany St., Rm. K-701, Boston, MA 02118. Tel.: 617-638-4173; Fax: 617-638-4176; E-mail: dfaller@bu.edu.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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