The molecular mechanism of boric acid toxicity in human prostate cancer cells

• Main Author: Barranco, Wade Thomas
• Format: Dissertation
• Language: English
• Published: ProQuest Dissertations & Theses 01-01-2006
• Subjects: Toxicology
• ISBN: 0542967448; 9780542967443

The objective of this study was to define a molecular mechanism through which boric acid induces cellular toxicity. With dietary boron displaying a capacity to reduce prostate cancer incidence, prostate cancer cells were selected as the experimental model for toxic assessment. In the cancerous prostate cell, toxic levels of boric acid were shown to: (1) preferentially inhibit prostate cancer cell (DU-145 and LNCaP) proliferation versus non-tumorgenic prostate lines (RWPE-1 and PWR-1E), while failing to induce cell death, (2) have insignificant effects on mitotic stage distribution and mitochondrial activity, (3) display enhanced potency for proliferative breakdown and intracellular calcium signaling disruption, with respect to the structural analog methylboronic acid, suggesting the necessity of 3 hydroxyl groups in the molecular interactions causing growth inhibition, (4) reduce cell sensitivity to NAD +- and mechanical stress-induced intracellular calcium release, following 8 day exposure (250 & 1000 μM), while displaying weaker effects on the stimulatory capacity of NADP+; whereas 6-minute exposures (10-40 mM) blocked the calcium stimulatory capacity of both NAD+ and NADP+, (5) redistribute intracellular calcium into subcellular vesicles, while increasing CD38 protein expression, (6) increase cell granularity, intracellular vesicle content and spreading, while decreasing cell volume, (7) up-regulate β-galactosidase activity, suggesting a conversion into a senescent-like entity, (8) dose-dependently reduce expression of cyclins A-E and MAPK proteins, thus connecting the absence of their mitogenic roles during observed proliferative inhibition, (9) reduce cell adhesion, migration and invasion potential, while inducing filopodia retraction, collectively leading to a loss in metastatic potential, (10) cause cell-dependent media acidosis correlating with an accumulation of LAMP-2-negative acidic compartments, (11) enhance genistein, seleno-l-methionine, and ionizing radiation cell kill, presumably by way of Bcl-2 protein down-regulation, (12) have an inverse correlation between groundwater concentrations, and prostate cancer incidence/mortality in Texas counties. In conclusion, boric acid, by disrupting the NAD+-sensitive intracellular calcium signaling cascade, induces a cell death-independent proliferative inhibition which ultimately transitions the DU-145 cell into a less malignant phenotype. Such findings shed light on the molecular pathways manipulated by boric acid in the mammalian cell, while giving credence to boric acid's chemopreventive role of human prostate cancer.