title: Betulinic Acid-Mediated Apoptosis in Human Prostate Cancer Cells Involves p53 and Nuclear Factor-Kappa B (NF-κB) Pathways.
abstract: Defects in p53 and nuclear factor-kappa B (NF-κB) signaling pathways are frequently observed in the initiation and development of various human malignancies, including prostate cancer. Clinical studies demonstrate higher expression of NF-κB/p65/RelA, NF-κB/p50/RelB, and cRel as well as downregulation of the p53 network in primary prostate cancer specimens and in metastatic tumors. Betulinic acid (BA), is a triterpenoid that has been reported to be an effective inducer of apoptosis through modification of several signaling pathways. Our objective was to investigate the pathways involved in BA-induced apoptosis in human prostate cancer cells. We employed the androgen-responsive LNCaP cells harboring wild-type p53, and androgen-refractory DU145 cells possessing mutated p53 with high constitutive NF-κB activity. Inhibition of cell survival by BA at 10 and 20 µM concentrations occurred as a result of alteration in Bax/Bcl-2 ratio in both cell lines that led to an increased cytochrome C release, caspase activation and poly(ADP)ribose polymerase (PARP) cleavage, leading to apoptosis. BA treatment resulted in stabilization of p53 through increase in phosphorylation at Ser15 in LNCaP cells, but not in DU145 cells, and induction of cyclin kinase inhibitor p21/Waf1 in both cell types. Furthermore, treatment of both prostate cancer cells with BA decreased the phosphorylation of IκB kinase (IKK)α and I-kappa-B-alpha (IκBα) inhibiting the nuclear location of NF-κB/p65 causing cytosolic accumulation and resulting in its decreased nuclear binding. We demonstrate that BA may induce apoptosis by stabilizing p53 and downregulating NF-κB pathway in human prostate cancer cells, irrespective of the androgen association, and therefore can potentially be developed as a molecule of interest in cancer chemoprevention.
authors.affiliation: Department of Urology, Case Western Reserve University, School of Medicine, Cleveland, OH 44106, USA. eswar.shankar@case.edu.|The Urology Institute, University Hospitals Cleveland Medical Center, Cleveland, OH 44106, USA. eswar.shankar@case.edu.
authors.forename: Eswar
authors.initials: E
authors.lastname: Shankar
authors.affiliation: Department of Urology, Case Western Reserve University, School of Medicine, Cleveland, OH 44106, USA. azhang@fhcrc.org.
authors.forename: Ailin
authors.initials: A
authors.lastname: Zhang
authors.affiliation: Department of Urology, Case Western Reserve University, School of Medicine, Cleveland, OH 44106, USA. dxf176@case.edu.
authors.forename: Daniel
authors.initials: D
authors.lastname: Franco
authors.affiliation: Department of Urology, Case Western Reserve University, School of Medicine, Cleveland, OH 44106, USA. sanjay.gupta@case.edu.|The Urology Institute, University Hospitals Cleveland Medical Center, Cleveland, OH 44106, USA. sanjay.gupta@case.edu.|Department of Urology, Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, OH 44106, USA. sanjay.gupta@case.edu.|Department of Nutrition, Case Western Reserve University, Cleveland, OH 44106, USA. sanjay.gupta@case.edu.|Division of General Medical Sciences, Case Comprehensive Cancer Center, Cleveland, OH 44106, USA. sanjay.gupta@case.edu.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Gupta
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D053938:DNA Fragmentation; D004354:Drug Screening Assays, Antitumor; D059585:G1 Phase Cell Cycle Checkpoints; D006801:Humans; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D053978:Pentacyclic Triterpenes; D011471:Prostatic Neoplasms / Q000188:drug therapy; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction; D014315:Triterpenes / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D000094062:Betulinic Acid
chemical_list: D000970:Antineoplastic Agents; C494826:BAX protein, human; C000595707:BCL2 protein, human; D016328:NF-kappa B; D053978:Pentacyclic Triterpenes; D019253:Proto-Oncogene Proteins c-bcl-2; C495901:TP53 protein, human; D014315:Triterpenes; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D000094062:Betulinic Acid
keywords: apoptosis; betulinic acid; chemoprevention; prostate cancer; triterpenoid