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Boric acid inhibits stored Ca2+ release in DU-145 prostate cancer cells

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Abstract

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 100μM, 60% at 250μM, and 97% at 1,000μM BA. NAD+-induced Ca2+ transients were partly inhibited at 250μM BA and completely at 1,000μM BA, whereas both NADP+ and mechanically induced transients were inhibited by 1,000μM BA. Expression of CD38 protein increased in proportion to BA exposure (0–1,000μM). 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 1,000μM BA. The BA analog, methylboronic acid (MBA; 250 and 1,000μM), 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.

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Acknowledgments

We wish to thank Michael Gulrajani in charge of the UCLA Jonsson Comprehensive Cancer Center (JCCC) and Center for AIDS Research Flow Cytometry Core Facility. This facility is supported by the National Institutes of Health awards CA-16042 and AI-28697 and by the JCCC, the UCLA AIDS Institute, and the David Geffen School of Medicine at UCLA.

Funding

The work for this grant was funded in part by University of California Toxic Substances Research and Training Program and the US Army Medical Research and Material Command Prostate Cancer Research Program Idea Grant to C.E., DAMD 17-03-0067.

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Authors and Affiliations

  1. Department of Pulmonary Medicine, Baylor College of Medicine, One Baylor Plaza, Suite 520B, Houston, TX, 77030, USA

    Wade T. Barranco

  2. Department of Environmental Health Sciences, University of California, Box 9517720, 650 Young Dr. South, Los Angeles, CA, 90095, USA

    Danny H. Kim & Curtis D. Eckhert

  3. Department of Neurobiology, University of California, Box 951763, Center for the Health Sciences, 650 Young Dr. South, Los Angeles, CA, 90095, USA

    Salvatore L. Stella Jr.

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  1. Wade T. Barranco
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  4. Curtis D. Eckhert
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Correspondence to Curtis D. Eckhert.

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Barranco, W.T., Kim, D.H., Stella Jr., S.L. et al. Boric acid inhibits stored Ca2+ release in DU-145 prostate cancer cells. Cell Biol Toxicol 25, 309–320 (2009). https://doi.org/10.1007/s10565-008-9085-7

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