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Fenretinide-induced Caspase 3 Activity Involves Increased Protein Stability in a Mechanism Distinct from Reactive Oxygen Species Elevation¹

Department of Biochemistry and Molecular Biology [A. M. D., T-C. H., J. M. W.] and the Brander Cancer Institute [T-C. H., G. J., F. T., Z. D., J. M. W.], New York Medical College, Valhalla, New York 10595

Fenretinide (4-HPR) is a synthetic retinoid that displays a broad range of biological effects and has also demonstrated clinical efficacy as a chemopreventative agent. One cellular activity of 4-HPR is its ability to induce apoptosis. This effect has been proposed to relate to changes in intracellular reactive oxygen species. We show herein that a 1-h treatment of HL-60 cells with 4-HPR led to a dose-dependent increase in hydroperoxides. Pretreatment of cells with the antioxidant vitamin C abolished apoptosis, measured as the appearance of the sub-G₁ peak, in 4-HPR-treated cells. The retinoid also elicited a 3.6-fold increase in caspase 3 activity; however, this increase was not affected by vitamin C treatment. Analysis of caspase 3 protein expression by Western blot analysis revealed that 4-HPR resulted in a significant increase in the appearance of the active p17 subunit without effecting a concomitant change in p32 procaspase 3 levels. Studies on de novo synthesis and stability of caspase 3 by pulse-chase and immunoprecipitation methods show that 4-HPR-treated samples had decreased incorporation of radioactive amino acid precursors into newly synthesized procaspase 3 but, during the chase (for up to 9 h), had more labeled caspase 3 remaining when compared with controls. These studies suggest that 4-HPR may effect changes in caspase 3 activity by modulating changes in zymogen stability by a mechanism distinct from the retinoid-elicited increase in reactive oxygen species.

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