Phenylbutyl isoselenocyanate induces reactive oxygen species to inhibit androgen receptor and to initiate p53-mediated apoptosis in LNCaP prostate cancer cells

Wei Wu, Deepkamal Karelia, Kartick Pramanik, Shantu Amin, Arun Sharma, Cheng Jiang, Junxuan Lu

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Abstract

Previous studies have established the in vivo bioavailability and efficacious dosages of phenylbutyl isoselenocyanate (ISC-4), a selenium-substituted isothiocyanate, against mouse xenograft models of human melanoma and colorectal cancer. To explore its potential attributes against prostate cancer, we treated human LNCaP prostate cancer cells with ISC-4 and examined their apoptosis responses, and interrogated the signaling mechanisms through pharmacological and siRNA knockdown approaches. Our results show that ISC-4 was more potent at inducing apoptosis than its sulfur analog phenylbutyl isothiocyanate (PBITC) without suppressing protein kinase AKT Ser 473 phosphorylation. ISC-4 induced apoptosis in concentration- and time-dependent manners, and the apoptosis execution was attenuated by pre-incubation with a pan caspase inhibitor. ISC-4 decreased the abundance of androgen receptor (AR) and its best known target prostate specific antigen (PSA) without decreasing their steady state mRNA. ISC-4 upregulated the abundance of p53 protein and its Ser 15 -phosphorylative activation, and that of DNA double strand break marker Ser 139 -p-H2A.X coincident with apoptotic exposure. Similar to the rapid induction of reactive oxygen species (ROS) by isothiocyanates, ISC-4 increased dihydroethidium-detectable signals in LNCaP cells. Pre-incubation with ROS scavenger N-acetyl-l-cysteine preserved AR and PSA abundance, markedly reduced ISC-4-induced apoptosis and attenuated p53 Ser phosphorylation, p21Cip1, and p-H2A.X. Furthermore, siRNA knockdown of p53 did not suppress ROS production, but decreased ISC-4-induced apoptosis. Knocking down p53-targets PUMA and Bax exerted greater protective effect on ISC-4-induced apoptosis than depleting p21Cip1. In summary, ISC-4 inhibited LNCaP cell growth and survival with ROS-mediated suppression of AR axis signaling and induction of p53-PUMA-Bax mitochondrial apoptosis.

Original languageEnglish (US)
Pages (from-to)1055-1066
Number of pages12
JournalMolecular Carcinogenesis
Volume57
Issue number8
DOIs
StatePublished - Aug 1 2018

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Androgen Receptors
Reactive Oxygen Species
Prostatic Neoplasms
Apoptosis
Prostate-Specific Antigen
Small Interfering RNA
Phosphorylation
Isothiocyanates
Caspase Inhibitors
Double-Stranded DNA Breaks
ISC-4 compound
Selenium
Sulfur
Heterografts
Protein Kinases
Biological Availability
Cysteine
Colorectal Neoplasms
Melanoma
Cell Survival

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cancer Research

Cite this

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title = "Phenylbutyl isoselenocyanate induces reactive oxygen species to inhibit androgen receptor and to initiate p53-mediated apoptosis in LNCaP prostate cancer cells",
abstract = "Previous studies have established the in vivo bioavailability and efficacious dosages of phenylbutyl isoselenocyanate (ISC-4), a selenium-substituted isothiocyanate, against mouse xenograft models of human melanoma and colorectal cancer. To explore its potential attributes against prostate cancer, we treated human LNCaP prostate cancer cells with ISC-4 and examined their apoptosis responses, and interrogated the signaling mechanisms through pharmacological and siRNA knockdown approaches. Our results show that ISC-4 was more potent at inducing apoptosis than its sulfur analog phenylbutyl isothiocyanate (PBITC) without suppressing protein kinase AKT Ser 473 phosphorylation. ISC-4 induced apoptosis in concentration- and time-dependent manners, and the apoptosis execution was attenuated by pre-incubation with a pan caspase inhibitor. ISC-4 decreased the abundance of androgen receptor (AR) and its best known target prostate specific antigen (PSA) without decreasing their steady state mRNA. ISC-4 upregulated the abundance of p53 protein and its Ser 15 -phosphorylative activation, and that of DNA double strand break marker Ser 139 -p-H2A.X coincident with apoptotic exposure. Similar to the rapid induction of reactive oxygen species (ROS) by isothiocyanates, ISC-4 increased dihydroethidium-detectable signals in LNCaP cells. Pre-incubation with ROS scavenger N-acetyl-l-cysteine preserved AR and PSA abundance, markedly reduced ISC-4-induced apoptosis and attenuated p53 Ser phosphorylation, p21Cip1, and p-H2A.X. Furthermore, siRNA knockdown of p53 did not suppress ROS production, but decreased ISC-4-induced apoptosis. Knocking down p53-targets PUMA and Bax exerted greater protective effect on ISC-4-induced apoptosis than depleting p21Cip1. In summary, ISC-4 inhibited LNCaP cell growth and survival with ROS-mediated suppression of AR axis signaling and induction of p53-PUMA-Bax mitochondrial apoptosis.",
author = "Wei Wu and Deepkamal Karelia and Kartick Pramanik and Shantu Amin and Arun Sharma and Cheng Jiang and Junxuan Lu",
year = "2018",
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T1 - Phenylbutyl isoselenocyanate induces reactive oxygen species to inhibit androgen receptor and to initiate p53-mediated apoptosis in LNCaP prostate cancer cells

AU - Wu, Wei

AU - Karelia, Deepkamal

AU - Pramanik, Kartick

AU - Amin, Shantu

AU - Sharma, Arun

AU - Jiang, Cheng

AU - Lu, Junxuan

PY - 2018/8/1

Y1 - 2018/8/1

N2 - Previous studies have established the in vivo bioavailability and efficacious dosages of phenylbutyl isoselenocyanate (ISC-4), a selenium-substituted isothiocyanate, against mouse xenograft models of human melanoma and colorectal cancer. To explore its potential attributes against prostate cancer, we treated human LNCaP prostate cancer cells with ISC-4 and examined their apoptosis responses, and interrogated the signaling mechanisms through pharmacological and siRNA knockdown approaches. Our results show that ISC-4 was more potent at inducing apoptosis than its sulfur analog phenylbutyl isothiocyanate (PBITC) without suppressing protein kinase AKT Ser 473 phosphorylation. ISC-4 induced apoptosis in concentration- and time-dependent manners, and the apoptosis execution was attenuated by pre-incubation with a pan caspase inhibitor. ISC-4 decreased the abundance of androgen receptor (AR) and its best known target prostate specific antigen (PSA) without decreasing their steady state mRNA. ISC-4 upregulated the abundance of p53 protein and its Ser 15 -phosphorylative activation, and that of DNA double strand break marker Ser 139 -p-H2A.X coincident with apoptotic exposure. Similar to the rapid induction of reactive oxygen species (ROS) by isothiocyanates, ISC-4 increased dihydroethidium-detectable signals in LNCaP cells. Pre-incubation with ROS scavenger N-acetyl-l-cysteine preserved AR and PSA abundance, markedly reduced ISC-4-induced apoptosis and attenuated p53 Ser phosphorylation, p21Cip1, and p-H2A.X. Furthermore, siRNA knockdown of p53 did not suppress ROS production, but decreased ISC-4-induced apoptosis. Knocking down p53-targets PUMA and Bax exerted greater protective effect on ISC-4-induced apoptosis than depleting p21Cip1. In summary, ISC-4 inhibited LNCaP cell growth and survival with ROS-mediated suppression of AR axis signaling and induction of p53-PUMA-Bax mitochondrial apoptosis.

AB - Previous studies have established the in vivo bioavailability and efficacious dosages of phenylbutyl isoselenocyanate (ISC-4), a selenium-substituted isothiocyanate, against mouse xenograft models of human melanoma and colorectal cancer. To explore its potential attributes against prostate cancer, we treated human LNCaP prostate cancer cells with ISC-4 and examined their apoptosis responses, and interrogated the signaling mechanisms through pharmacological and siRNA knockdown approaches. Our results show that ISC-4 was more potent at inducing apoptosis than its sulfur analog phenylbutyl isothiocyanate (PBITC) without suppressing protein kinase AKT Ser 473 phosphorylation. ISC-4 induced apoptosis in concentration- and time-dependent manners, and the apoptosis execution was attenuated by pre-incubation with a pan caspase inhibitor. ISC-4 decreased the abundance of androgen receptor (AR) and its best known target prostate specific antigen (PSA) without decreasing their steady state mRNA. ISC-4 upregulated the abundance of p53 protein and its Ser 15 -phosphorylative activation, and that of DNA double strand break marker Ser 139 -p-H2A.X coincident with apoptotic exposure. Similar to the rapid induction of reactive oxygen species (ROS) by isothiocyanates, ISC-4 increased dihydroethidium-detectable signals in LNCaP cells. Pre-incubation with ROS scavenger N-acetyl-l-cysteine preserved AR and PSA abundance, markedly reduced ISC-4-induced apoptosis and attenuated p53 Ser phosphorylation, p21Cip1, and p-H2A.X. Furthermore, siRNA knockdown of p53 did not suppress ROS production, but decreased ISC-4-induced apoptosis. Knocking down p53-targets PUMA and Bax exerted greater protective effect on ISC-4-induced apoptosis than depleting p21Cip1. In summary, ISC-4 inhibited LNCaP cell growth and survival with ROS-mediated suppression of AR axis signaling and induction of p53-PUMA-Bax mitochondrial apoptosis.

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