Cells Preconditioned with Mild, Transient UVA Irradiation Acquire Resistance to Oxidative Stress and UVA-induced Apoptosis

Abstract

The preconditioned cells transported GS-HNE into the medium at a rate about 2-fold higher than the controls and the transport was inhibited (65%) by coating the cells with anti-RLIP76 IgG. Upon treatment with xanthine/xanthine oxidase (XA/XO), 4-HNE, or prolonged UVA exposure, the control cells showed a sustained activation of c-Jun N-terminal kinase (JNK) and apoptosis. However, in the UVA-preconditioned cells, apoptosis was not observed, and JNK activation was inhibited. This resistance of preconditioned cells to XA/ XO-, 4-HNE-, or UVA-induced apoptosis could be abrogated when these cells were coated with anti-RLIP76 IgG to block the efflux of GS-HNE. These studies strongly suggest a role of 4-HNE in UVA-mediated apoptosis.

Self-regulatory role of 4-hydroxynonenal in signaling for stress-induced programmed cell death

“…In recent years, studies in our laboratory have focused on the mechanisms of HNE-induced signaling and its regulation by enzymes which determine the intracellular concentration of HNE. These studies indicate an important role of HNE in signaling for apoptosis induced by stressors including H 2 O 2 , UV, heat, and oxidant chemicals such as naphthalene or doxorubicin and that apoptosis induced by these agents can be inhibited in cells transfected with enzymes that limit the intracellular concentrations of HNE [7][8][9]47,77]. For example, the overexpression of GSTA4-4 or GST5.8, which detoxify HNE, inhibits apoptosis induced by xanthine/xanthine oxidase, H 2 O 2 , UV, and doxorubicin [9].…”

“…These studies indicate an important role of HNE in signaling for apoptosis induced by stressors including H 2 O 2 , UV, heat, and oxidant chemicals such as naphthalene or doxorubicin and that apoptosis induced by these agents can be inhibited in cells transfected with enzymes that limit the intracellular concentrations of HNE [7][8][9]47,77]. For example, the overexpression of GSTA4-4 or GST5.8, which detoxify HNE, inhibits apoptosis induced by xanthine/xanthine oxidase, H 2 O 2 , UV, and doxorubicin [9]. Furthermore, these studies indicate that lowering of the intracellular concentration of HNE by overexpression of GSTA4-4 results in profound changes in the expression of a multitude of genes and transformation of adherent HLE-B3 into suspended rounded cells which proliferate at a much faster rate [45].…”

“…Taken together with the previously reported induction of gluatmate cysteine ligase and GSH biosynthesis [89] in cells exposed to HNE are consistent with the idea of a protective role of HNE. Thus, HNE-induced translocation of Daxx from the nucleus to cytoplasm, and release of free HSF1 in the nucleus may have major implications for the defense mechanisms during stress-mediated signaling, particularly by stressors such as UV radiation, heat shock, or oxidants which invariably increase the cellular concentration of HNE [9].…”

“…Since HNE concentrations in cells are increased in stressed cells and that it is a common denominator in the mechanisms of apoptosis caused by the diverse forms of oxidative stress including UV [7,9], it is likely to affect the expression and/or activation of p53. If so, HNE-mediated activation of p53 may be one of the mechanisms responsible for HNE-induced apoptosis reported in many cell types [7][8][9][12][13][14][15][16][46][47][48]61]. Our recent studies are in accordance with this prediction.…”

“…These studies have opened a new area in the field of ROS-induced signaling focusing on the regulatory roles of the enzymes involved in the formation and metabolism of HNE. Recent studies in this area have shown that enzymes such as glutathione S-transferases (GSTs), aldehyde dehydrogenases, aldose reductase, glutathione peroxidase, and RalBP1 (Ral-binding protein 1) that are among the major determinants of intracellular levels of HNE can modulate stress-induced signaling for programmed cell death [2][3][4][5][6][7][8][9][10]. Some of these studies [11][12][13][14] seem to have major clinical implications particularly in regard to cancer chemotherapy [11,12], inhibition of tumor growth [13], and sepsis [14] as discussed briefly later in this review.…”