Boric acid inhibits stored Ca2+ release in DU-145 prostate cancer cells.
Boron (B) is a developmental and reproductive toxin. It is also essential for some organisms. Plants use uptake and efflux transport proteins to maintain homeostasis, and in humans, boron has been reported to reduce prostate cancer. Ca2+ signaling is one of the primary mechanisms used by cells to respond to their environment. In this paper, we report that boric acid (BA) inhibits NAD+ and NADP+ as well as mechanically induced release of stored Ca2+ in growing DU-145 prostate cancer cells. Cell proliferation was inhibited by 30% at 100 microM, 60% at 250 microM, and 97% at 1,000 microM BA. NAD+-induced Ca2+ transients were partly inhibited at 250 microM BA and completely at 1,000 microM BA, whereas both NADP+ and mechanically induced transients were inhibited by 1,000 microM BA. Expression of CD38 protein increased in proportion to BA exposure (0-1,000 microM). In vitro mass spectrometry analysis showed that BA formed adducts with the CD38 products and Ca2+ channel agonists cyclic adenosine diphosphate ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP). Vesicles positive for the Ca2+ fluorophore fluo-3 acetoxymethyl ester accumulated in cells exposed to 250 and 1,000 microM BA. The BA analog, methylboronic acid (MBA; 250 and 1,000 microM), did not inhibit cell proliferation or NAD+, NADP+, or mechanically stimulated Ca2+ store release. Nor did MBA increase CD38 expression or cause the formation of intracellular vesicles. Thus, mammalian cells can distinguish between BA and its synthetic analog MBA and exhibit graded concentration-dependent responses. Based on these observations, we hypothesize that toxicity of BA stems from the ability of high concentrations to impair Ca2+ signaling.
Department of Pulmonary Medicine, Baylor College of Medicine, One Baylor Plaza, Suite 520B, Houston, TX 77030, USA.
Wade T
WT
Barranco
Danny H
DH
Kim
Salvatore L
SL
Stella
Curtis D
CD
Eckhert
D051997:ADP-ribosyl Cyclase 1 / Q000378:metabolism; D001888:Boric Acids / Q000633:toxicity*; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D036563:Cyclic ADP-Ribose / Q000378:metabolism; D006801:Humans; D008297:Male; D009243:NAD / Q000378:metabolism; D009249:NADP / Q000378:metabolism
D001888:Boric Acids; D009243:NAD; D036563:Cyclic ADP-Ribose; D009249:NADP; D051997:ADP-ribosyl Cyclase 1; C032688:boric acid; D002118:Calcium