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 Ser473 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 Ser15 -phosphorylative activation, and that of DNA double strand break marker Ser139 -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.

journal_name

Mol Carcinog

journal_title

Molecular carcinogenesis

authors

Wu W,Karelia D,Pramanik K,Amin SG,Sharma AK,Jiang C,Lu J

doi

10.1002/mc.22825

subject

Has Abstract

pub_date

2018-08-01 00:00:00

pages

1055-1066

issue

8

eissn

0899-1987

issn

1098-2744

journal_volume

57

pub_type

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