Suppression of human prostate cancer PC-3 cell growth by N-acetylcysteine involves over-expression of Cyr61.
N-Acetylcysteine (NAC), sulfidryl-containing thiol antioxidant, has been heralded as chemopreventive agent, generally because of its ability to scavenge free radicals. It also suppresses the proliferation of many cancer cells; however, the antiproliferative mechanism(s) remain to be fully elucidated. In this study, we investigated a growth-suppressive mechanism of NAC action in androgen-independent prostate carcinoma PC-3 cells. NAC (≥ 1mM) inhibited the proliferation of PC-3 cells in a dose- and time-dependent manner. Moreover, NAC treatment suppressed the activation of NF-κB induced by IKK-β as detected by the NF-κB reporter gene assay. NAC exerted a biphasic effect on the intracellular ROS levels depending on incubation time; the antioxidant effect was seen within 2h after NAC treatment, however, a pro-oxidant effect was evident after 48 h treatment. In addition to these effects, NAC treatment elicited a dose- and time-dependent increase in the Cyr61 expression that was accompanied by an increase in its mRNA and blocked by cycloheximide pretreatment. Importantly, NAC treatment caused an early but transient activation of Akt and Erk1/2. The NAC-induced increase in Cyr61 protein levels was suppressed by the PI3K inhibitor (Ly294002) and, to a lesser extent, MEK/Erk1/2 inhibitor (PD98059). Taken together, our data suggest that the antiproliferative effect of NAC is partially mediated by intracellular ROS production, the inhibition of NF-κB activity, and the activation of PI3K- and/or MEK/Erk-related intracellular signaling pathways, which lead to up-regulation of Cyr61 expression.
Department of Biochemistry, College of Medicine, Soonchunhyang University, Cheonan, Republic of Korea.
Yoon-Jin
YJ
Lee
David M
DM
Lee
Chang-Ho
CH
Lee
Sue-Hak
SH
Heo
Seong Youn
SY
Won
Jae-Hyuk
JH
Im
Moon-Kyun
MK
Cho
Hae-Seon
HS
Nam
Sang-Han
SH
Lee
D000111:Acetylcysteine / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D002277:Carcinoma / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D055515:Cysteine-Rich Protein 61 / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D017930:Genes, Reporter; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D008297:Male; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000517:prevention & control; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects*
D000970:Antineoplastic Agents; D000975:Antioxidants; C501848:CCN1 protein, human; D055515:Cysteine-Rich Protein 61; D016328:NF-kappa B; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; D000111:Acetylcysteine