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

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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

Fingerprint

Arsenicals
Telomerase
Reactive Oxygen Species
Chemical activation
Apoptosis
Proteins
3-methoxy-4-methylamphetamine
Peroxides
DNA Fragmentation
Dynamic mechanical analysis
Cytotoxicity
Chromosomes
Gene expression
Proteolysis
Condensation
Cell Survival

Keywords

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

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

Cite this

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title = "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",
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.",
keywords = "Apoptosis, Arsenics, Heat shock protein 90, Heme oxygenase 1, ROS, Telomerase",
author = "Shen, {Shing Chuan} and Yang, {Liang Yo} and Lin, {Hui Yi} and Wu, {Chin Yen} and Su, {Tsung Hsien} and Chen, {Yen Chou}",
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T1 - 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

AU - Shen, Shing Chuan

AU - Yang, Liang Yo

AU - Lin, Hui Yi

AU - Wu, Chin Yen

AU - Su, Tsung Hsien

AU - Chen, Yen Chou

PY - 2008/6/1

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N2 - 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.

AB - 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.

KW - Apoptosis

KW - Arsenics

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KW - Heme oxygenase 1

KW - ROS

KW - Telomerase

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