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Molecules 2017, 22(2), 264; doi:10.3390/molecules22020264

Betulinic Acid-Mediated Apoptosis in Human Prostate Cancer Cells Involves p53 and Nuclear Factor-Kappa B (NF-κB) Pathways

1
Department of Urology, Case Western Reserve University, School of Medicine, Cleveland, OH 44106, USA
2
The Urology Institute, University Hospitals Cleveland Medical Center, Cleveland, OH 44106, USA
3
Department of Urology, Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, OH 44106, USA
4
Department of Nutrition, Case Western Reserve University, Cleveland, OH 44106, USA
5
Division of General Medical Sciences, Case Comprehensive Cancer Center, Cleveland, OH 44106, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Santosh K. Katiyar
Received: 16 January 2017 / Revised: 6 February 2017 / Accepted: 8 February 2017 / Published: 10 February 2017
(This article belongs to the Special Issue Cancer Chemoprevention)
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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. View Full-Text
Keywords: prostate cancer; chemoprevention; apoptosis; betulinic acid; triterpenoid prostate cancer; chemoprevention; apoptosis; betulinic acid; triterpenoid
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Shankar, E.; Zhang, A.; Franco, D.; Gupta, S. Betulinic Acid-Mediated Apoptosis in Human Prostate Cancer Cells Involves p53 and Nuclear Factor-Kappa B (NF-κB) Pathways. Molecules 2017, 22, 264.

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