Altholactone Inhibits NF-κB and STAT3 Activation and Induces Reactive Oxygen Species-Mediated Apoptosis in Prostate Cancer DU145 Cells.
Altholactone, a natural compound isolated from Goniothalamus spp., has demonstrated anti-inflammatory and anticancer activities, but its molecular mechanisms are still not fully defined. Nuclear factor kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3) play pivotal roles in the cell survival of many human tumors. The objective of this study was to elucidate the mechanism of action of altholactone against prostate cancer DU145 cells and to evaluate whether its effects are mediated by inhibition of NF-κB and STAT3 activity. Altholactone inhibited proliferation of DU145 cells and induced cell cycle arrest in S phase and triggered apoptosis. Reporter assays revealed that altholactone repressed p65- and TNF-α-enhanced NF-κB transcriptional activity and also inhibited both constitutive and IL-6-induced transcriptional activity of STAT3. Consistent with this, altholactone down-regulated phosphorylation of STAT3 and moreover, decreased constitutively active mutant of STAT3 (STAT3C)-induced transcriptional activity. Altholactone treatment also results in down-regulation of STAT3 target genes such as survivin, and Bcl-2 followed by up regulation of pro-apoptotic Bax protein. However, pre-treatment with the antioxidant N-acetylcysteine (NAC) significantly inhibited the activation of Bax and prevented down-regulation of STAT3 target genes. Collectively, our findings suggest that altholactone induces DU145 cells death through inhibition of NF-κB and STAT3 activity.
['Jiang|Chunwa|C|', 'Masood|Muqaddas|M|', 'Rasul|Azhar|A|', 'Wei|Wei|W|', 'Wang|Ya|Y|', 'Ali|Muhammad|M|', 'Mustaqeem|Muhammad|M|', 'Li|Jiang|J|', 'Li|Xiaomeng|X|']
D000972:Antineoplastic Agents, Phytogenic D017209:Apoptosis D045744:Cell Line, Tumor D049109:Cell Proliferation D002470:Cell Survival D004354:Drug Screening Assays, Antitumor D005663:Furans D054335:Goniothalamus D006801:Humans D008297:Male D016328:NF-kappa B D011471:Prostatic Neoplasms D011753:Pyrones D017382:Reactive Oxygen Species D050796:STAT3 Transcription Factor D015398:Signal Transduction
altholactone NF-κB STAT3 prostate cancer natural compound