Reactive oxygen species-dependent HSP90 protein cleavage participates in arsenical As(+3)- and MMA(+3)-induced apoptosis through inhibition of telomerase activity via JNK activation.
The effects of six arsenic compounds including As(+3), MMA(+3), DMA(+3), As(+5), MMA(+5), and DMA(+5) on the viability of NIH3T3 cells were examined. As(+3) and MMA(+3), but not the others, exhibited significant cytotoxic effects in NIH3T3 cells through apoptosis induction. The apoptotic events such as DNA fragmentation and chromosome condensation induced by As(+3) and MMA(+3) were prevented by the addition of NAC and CAT, and induction of HO-1 gene expression in accordance with cleavage of the HSP90 protein, and suppression of telomerase activity were observed in NIH3T3 cells under As(+3) and MMA(+3) treatments. An increase in the intracellular peroxide level was examined in As(+3)- and MMA(+3)-treated NIH3T3 cells, and As(+3)- and MMA(+3)-induced apoptotic events were blocked by NAC, CAT, and DPI addition. HSP90 inhibitors, GA and RD, significantly attenuated the telomerase activity in NIH3T3 cells with an enhancement of As(+3)- and MMA(+3)-induced cytotoxicity. Suppression of JNKs significantly inhibited As(+3)- and MMA(+3)-induced apoptosis by blocking HSP90 protein cleavage and telomerase reduction in NIH3T3 cells. Furthermore, Hb, SnPP, and dexferosamine showed no effect against As(+3)- and MMA(+3)-induced apoptosis, and overexpression of HO-1 protein or inhibition of HO-1 protein expression did not affect the apoptosis induced by As(+3) or MMA(+3). These data provide the first evidence to indicate that apoptosis induced by As(+3) and MMA(+3) is mediated by an ROS-dependent degradation of HSP90 protein and reduction of telomerase via JNK activation, and HO-1 induction might not be involved.
Shen
Shing-Chuan
SC
Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan.
Yang
Liang-Yo
LY
Lin
Hui-Yi
HY
Wu
Chin-Yen
CY
Su
Tsung-Hsien
TH
Chen
Yen-Chou
YC
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001152:Arsenicals / Q000494:pharmacology*; D001483:Base Sequence; D017931:DNA Primers; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics; D006868:Hydrolysis; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D051379:Mice; D041681:NIH 3T3 Cells; D017382:Reactive Oxygen Species / Q000378:metabolism*; D019098:Telomerase / Q000037:antagonists & inhibitors*
D001152:Arsenicals; D017931:DNA Primers; D018841:HSP90 Heat-Shock Proteins; D017382:Reactive Oxygen Species; D006419:Heme Oxygenase (Decyclizing); D048670:MAP Kinase Kinase 4; D019098:Telomerase