Role of Lipid Peroxidation in Cellular Responses to d,l-Sulforaphane, a Promising Cancer Chemopreventive Agent

摘要

D,L-Sulforaphane (SFN), a synthetic analogue of the broccoli-derived L-isomer, is a highlynpromising cancer chemopreventive agent substantiated by inhibition of chemically induced cancer in rodentsnand prevention of cancer development and distant site metastasis in transgenic mouse models of cancer. SFNnis also known to inhibit growth of human cancer cells in association with cell cycle arrest and reactive oxygennspecies-dependent apoptosis, but the mechanism of these cellular responses to SFN exposure is not fullynunderstood. Because 4-hydroxynonenal (4-HNE), a product of lipid peroxidation (LPO), the formation ofnwhich is regulated by hGSTA1-1, assumes a pivotal role in oxidative stress-induced signal transduction, weninvestigated its contribution in growth arrest and apoptosis induction by SFN using HL60 and K562 humannleukemic cell lines as a model. The SFN-induced formation of 4-HNE was suppressed in hGSTA1-1-noverexpressing cells, which also acquired resistance to SFN-induced cytotoxicity, cell cycle arrest, andnapoptosis. While resistance to SFN-induced cell cycle arrest by ectopic expression of hGSTA1-1 wasnassociated with changes in levels of G2/M regulatory proteins, resistance to apoptosis correlated with annincreased Bcl-xL/Bax ratio, inhibition of nuclear translocation ofAIF, and attenuated cytochrome c release inncytosol. The hGSTA1-1-overexpressing cells exhibited enhanced cytoplasmic export of Daxx, nuclearnaccumulation of transcription factors Nrf2 and HSF1, and upregulation of their respective client proteins,nγ-GCS and HSP70. These findings not only reveal a central role of 4-HNE in cellular responses to SFN butnalso reaffirm that 4-HNE contributes to oxidative stress-mediated signaling.