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

Shing Chuan Shen, Liang Yo Yang, Hui Yi Lin, Chin Yen Wu, Tsung Hsien Su, Yen Chou Chen

Research output: Contribution to journalArticlepeer-review

27 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)239-251
Number of pages13
JournalToxicology and Applied Pharmacology
Volume229
Issue number2
DOIs
Publication statusPublished - Jun 1 2008

Keywords

  • Apoptosis
  • Arsenics
  • Heat shock protein 90
  • Heme oxygenase 1
  • ROS
  • Telomerase

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

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