title: Inactivation of ATP citrate lyase by Cucurbitacin B: A bioactive compound from cucumber, inhibits prostate cancer growth.
abstract: Prostate cancer, a leading cause of cancer-related deaths in males, is well recognized as having late disease on-set (mostly at age 60-70) and showing slow/latent disease development, and strategies to prevent cancer formation in late manhood may have significant health impacts. Cucurbitacin B (CuB) is a naturally occurring compound that is found abundantly in cucumbers and other vegetables, and it is known to exert anti-cancer activities (primarily via apoptosis-induction) in several human cancers. However, its chemopreventive potential for prostate cancer has not yet been investigated. Here, we reported that CuB significantly and specifically inhibited prostate cancer cell growth with low IC50 (~0.3 μM; PC-3 and LNCaP), accompanied by marked apoptosis (Caspase 3/7 activation, PARP cleavage, increase of Annexin V-Alexa Fluor 488 (Alexa488)+ cells and accumulation of Sub-G0/G1 population), whereas normal human prostate epithelial cells (PrEC) were CuB-insensitive. Using a chemopreventive model, pre-treatment of mice with CuB (2 weeks before PC-3 prostate cancer cell implantation) significantly reduced the rate of in vivo tumor-formation. A 79% reduction in tumor size (accompanied by marked in situ apoptosis) was observed in the CuB-treated group (with no noticeable toxicity) vs. controls at day 31. Strikingly, mechanistic investigations demonstrated that CuB drove dose-dependent inhibition of ATP citrate lyase phosphorylation (ACLY; an important enzyme for cancer metabolism) both in vitro and in the CuB-chemopreventive mouse model. Importantly, ACLY over-expression abrogated CuB's apoptotic effects in prostate cancer cells, confirming ACLY as a direct target of CuB. Thus, CuB harbors potent chemopreventive activity for prostate cancer, and we revealed a novel anti-tumor mechanism of CuB via inhibition of ACYL signaling in human cancer.
authors.affiliation: Department of Urology, University of Pittsburgh Cancer Institute, University of Pittsburgh Medical College, University of Pittsburgh, Shadyside Medical Center, Suit G37, 5200 Centre Avenue, Pittsburgh, PA 15232, USA.
authors.forename: Yajuan
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of Urology, University of Pittsburgh Cancer Institute, University of Pittsburgh Medical College, University of Pittsburgh, Shadyside Medical Center, Suit G37, 5200 Centre Avenue, Pittsburgh, PA 15232, USA.
authors.forename: Mohammad Shyful
authors.initials: MS
authors.lastname: Islam
authors.affiliation: Department of Urology, University of Pittsburgh Cancer Institute, University of Pittsburgh Medical College, University of Pittsburgh, Shadyside Medical Center, Suit G37, 5200 Centre Avenue, Pittsburgh, PA 15232, USA.
authors.forename: Jiang
authors.initials: J
authors.lastname: Tian
authors.affiliation: Department of Pharmacology and Pharmacy, Li Ka Faculty of Medicine, University of Hong Kong, Hong Kong Special Administrative Region.
authors.forename: Vivian Wai Yan
authors.initials: VW
authors.lastname: Lui
authors.affiliation: Department of Urology, University of Pittsburgh Cancer Institute, University of Pittsburgh Medical College, University of Pittsburgh, Shadyside Medical Center, Suit G37, 5200 Centre Avenue, Pittsburgh, PA 15232, USA. Electronic address: dongx@upmc.edu.
authors.forename: Dong
authors.initials: D
authors.lastname: Xiao
mesh_terms: D001275:ATP Citrate (pro-S)-Lyase / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001685:Biological Factors / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018553:Cucumis sativus / Q000737:chemistry; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010766:Phosphorylation / Q000187:drug effects; D010936:Plant Extracts / Q000494:pharmacology; D011467:Prostate / Q000187:drug effects / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D014315:Triterpenes / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D001685:Biological Factors; D010936:Plant Extracts; D014315:Triterpenes; C041246:cucurbitacin B; D001275:ATP Citrate (pro-S)-Lyase
keywords: ATP citrate lyase; Apoptosis; Cucurbitacin B; Prostate cancer; Xenografts