title: Gossypol induces apoptosis by activating p53 in prostate cancer cells and prostate tumor-initiating cells.
abstract: Prostate cancer continues to represent a burgeoning medical problem in the United States. Recent studies suggest that gossypol, a bioactive phytochemical produced by cotton plants, is a promising agent against prostate cancer. The current studies were undertaken to examine the chemotherapeutic efficacy of gossypol on human prostate cancer cell lines and prostate tumor-initiating cells. Gossypol reduced the viability of three prostate cancer cell lines (LAPC4, PC3, and DU145) with an IC(50) between 3 and 5 micromol/L. Additionally, gossypol was effective at inhibiting prostate tumor-initiating cell-driven tumor growth in a nonobese diabetic/severe combined immunodeficient xenograft model. Our integrated molecular profiling approach encompassing proteomics, activated transcription factors, and genomics suggests that the decrease in viability was associated with increased DNA damage and the induction of apoptosis. Exposure of DU145 cells to gossypol (1-10 micromol/L) resulted in the activation of 13 proteins and 7 transcription factors, and the expression of 17 genes involved in the mitochondrial pathway of apoptosis. These studies show for the first time that gossypol treatment induces DNA damage and activates p53. Collectively, these data support the use of gossypol as a novel agent for prostate cancer.
authors.affiliation: Cancer Stem Cell Section, Laboratory of Cancer Prevention, Center for Cancer Research, National Cancer Institute at Frederick, NIH, Frederick, Maryland 21702, USA. volatesr@mail.nih.gov
authors.forename: Suresh R
authors.initials: SR
authors.lastname: Volate
authors.forename: Brian T
authors.initials: BT
authors.lastname: Kawasaki
authors.forename: Elaine M
authors.initials: EM
authors.lastname: Hurt
authors.forename: John A
authors.initials: JA
authors.lastname: Milner
authors.forename: Young S
authors.initials: YS
authors.lastname: Kim
authors.forename: Jeffrey
authors.initials: J
authors.lastname: White
authors.forename: William L
authors.initials: WL
authors.lastname: Farrar
mesh_terms: D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D003272:Contraceptive Agents, Male / Q000494:pharmacology; D006072:Gossypol / Q000494:pharmacology*; D006801:Humans; D018960:Hyaluronan Receptors / Q000096:biosynthesis; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D009368:Neoplasm Transplantation; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D003272:Contraceptive Agents, Male; D018960:Hyaluronan Receptors; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D006072:Gossypol