title: Mycotoxin verrucarin A inhibits proliferation and induces apoptosis in prostate cancer cells by inhibiting prosurvival Akt/NF-kB/mTOR signaling.
abstract: Trichothecenes are powerful mycotoxins that inhibit protein synthesis and induce ribotoxic stress response in mammalian cells. Verrucarin A (VC-A) is a Type D macrocyclic mycotoxin which inhibits cell proliferation and induces apoptosis in cancer cells. However, the antitumor activity of VC-A for prostate cancer cells has not been investigated. The objective of the present study was to determine the anticancer activity and its mechanism of action in hormone-responsive (LNCaP) and hormone-refractory (PC-3) carcinoma of the prostate (CaP) cell lines. VC-A strongly inhibited the proliferation and induced cell cycle arrest in G2/M phase associated with the inhibition of cell cycle regulatory proteins cyclin D, cyclin E, cyclin-dependent kinases (cdks) cdk2, cdk4, cdk6 and cdk inhibitors WAF1/21 and KIP1/27. VC-A also induced apoptosis in CaP cells as characterized by the cleavage of poly (ADP-ribose) polymerase (PARP-1), procaspases-3, -8 and -9 and the inhibition of Bcl-2 family proteins that regulate apoptosis (Bcl-2, Bcl-xL, Bax, Bak and Bad). In addition, VC-A also down-regulated the expression of prosurvival phospho-AKT (p-AKT), nuclear factor kappa B (NF-kB) (p65) and phospho-mammalian target of rapamycin (p-mTOR) signaling proteins. Taken together, these results demonstrated strong antiproliferative and apoptosis-inducing activity of verrucarin A against CaP cells through cell cycle arrest and inhibition of the prosurvival (antiapoptotic) AKT/NF-kB/mTOR signaling pathway.
authors.affiliation: Department of Surgery, Henry Ford Health System, Detroit, Michigan, USA.
authors.forename: Yongbo
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Surgery, Henry Ford Health System, Detroit, Michigan, USA.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Gao
authors.affiliation: Department of Surgery, Henry Ford Health System, Detroit, Michigan, USA.
authors.forename: Dorrah
authors.initials: D
authors.lastname: Deeb
authors.affiliation: Department of Internal Medicine, Henry Ford Health System, Detroit, Michigan, USA.
authors.forename: Yiguan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Internal Medicine, Henry Ford Health System, Detroit, Michigan, USA.
authors.forename: Jiajiu
authors.initials: J
authors.lastname: Shaw
authors.affiliation: Department of Internal Medicine, Henry Ford Health System, Detroit, Michigan, USA.
authors.forename: Frederick A
authors.initials: FA
authors.lastname: Valeriote
authors.affiliation: Department of Surgery, Henry Ford Health System, Detroit, Michigan, USA.
authors.forename: Subhash C
authors.initials: SC
authors.lastname: Gautam
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D015536:Down-Regulation / Q000187:drug effects; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D008297:Male; D009183:Mycotoxins / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism*; D011467:Prostate / Q000187:drug effects / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014255:Trichothecenes / Q000494:pharmacology*
chemical_list: D051017:Apoptosis Regulatory Proteins; D009183:Mycotoxins; D016328:NF-kappa B; D014255:Trichothecenes; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C005348:muconomycin A
keywords: Akt; NF-kB; apoptosis; mTOR; prostate cancer; verrucarin A