Mechanisms controlling cell cycle arrest and induction of apoptosis after 12-lipoxygenase inhibition in prostate cancer cells

• Published in: Cancer research (Chicago, Ill.) Vol. 62; no. 9; pp. 2721 - 2727
• Main Authors: PIDGEON, Graham P, KANDOUZ, Mustapha, MERAM, Anthony, HONN, Kenneth V
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.05.2002
• Subjects: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid - pharmacology; Antineoplastic agents; Apoptosis - drug effects; Apoptosis - physiology; bcl-2-Associated X Protein; bcl-X Protein; Biological and medical sciences; Biotin - analogs & derivatives; Biotin - pharmacology; Cell Cycle - drug effects; Cell Cycle - physiology; Cell Division - drug effects; Cell Division - physiology; Chemotherapy; Enzyme Inhibitors - pharmacology; Flavanones; Flavonoids - pharmacology; G1 Phase - drug effects; G1 Phase - physiology; Humans; Lipoxygenase Inhibitors; Male; Medical sciences; Phalloidine - analogs & derivatives; Phalloidine - pharmacology; Pharmacology. Drug treatments; Phosphorylation; Prostatic Neoplasms - enzymology; Prostatic Neoplasms - pathology; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-bcl-2 - metabolism; Retinoblastoma Protein - metabolism; S Phase - drug effects; S Phase - physiology; Tumor Cells, Cultured; Antineoplastic agent; Human; Cell proliferation; Urinary system disease; Prostate disease; Enzyme; Enzyme inhibitor; Malignant tumor; In vitro; Biological activity; Signal transduction; Arachidonate 12-lipoxygenase; Cell death; Cell cycle; Established cell line; Oxidoreductases; Lipoxygenase; Mechanism of action; Male genital diseases; Prostate; Tumor cell; Apoptosis
• ISSN: 0008-5472; 1538-7445

Extensive studies have implicated the role of dietary fatty acids in prostatecancer progression. Platelet-type 12-Lipoxygenase (12-LOX) has beenshown to regulate growth, metastasis, and angiogenesis of prostate cancer. The effect of two 12-LOX inhibitors, Baicalein and N-benzyl-N-hydroxy-5-phenylpentamide (BHPP), on the mechanisms controlling cell cycle progression and apoptosis were examined in two prostate cancer cell lines, PC3 and DU-145. Treatment with Baicalein or BHPP resulted in a dose-dependent decrease in cell proliferation, as measured by BrdUrd incorporation. This growth arrest was shown to be because of cell cycle inhibition at G0/G1, and was associated with suppression of cyclin D1 and D3 protein levels. PC3 cells also showed a strong decrease in phosphorylated retinoblastoma (pRB) protein, whereas the other retinoblastoma-associated proteins, p107 and p130, were inhibited in DU-145 cells. Treatment with 12-hydroxyeicosatetraenoic acid in the presence of Baicalein blocked loss of pRB, whereas 12(S)-HETE alone induced pRB expression. Treatment with either Baicalein or BHPP resulted in significant apoptosis in both cell lines as measured by terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling. DU-145 cells underwent apoptosis more rapidly than PC-3 cells. The mechanisms involved were decreased phosphorylation of Akt, loss of survivin and subsequent activation of caspase-3 and caspase-7 in each cell line, decreased Bcl-2 and Bcl-X(L) expression in DU-145, and a shift in Bcl-2/Bax levels favoring apoptosis in PC-3 cells. Addition of 12(S)-HETE protected both cell lines from Baicalein-induced apoptosis, whereas other LOX metabolites, 5(S)-HETE, or 15(S)-HETE did not. These results show that the 12-LOX pathway is a critical regulator of prostate cancer progression and apoptosis, by affecting various proteins regulating these processes. Therefore, inhibition of 12-LOX is a potential therapeutic agent in the treatment of prostate cancer.