Resveratrol derivatives increase cytosolic calcium by inhibiting plasma membrane ATPase and inducing calcium release from the endoplasmic reticulum in prostate cancer cells

Joshua A Peterson; Colton M Crowther; Merritt B Andrus; Jason D Kenealey

doi:10.1016/j.bbrep.2019.100667

Resveratrol derivatives increase cytosolic calcium by inhibiting plasma membrane ATPase and inducing calcium release from the endoplasmic reticulum in prostate cancer cells

Biochem Biophys Rep. 2019 Jul 20:19:100667. doi: 10.1016/j.bbrep.2019.100667. eCollection 2019 Sep.

Authors

Joshua A Peterson¹, Colton M Crowther², Merritt B Andrus², Jason D Kenealey¹

Affiliations

¹ Department of Nutrition, Dietetics and Food Science, Brigham Young University, Provo, UT, USA.
² Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT, USA.

Abstract

Resveratrol (RES) is a putative chemotherapeutic naturally found in grapes, peanuts, and Japanese knotweed. Previous studies demonstrate that RES modulates calcium signaling as part of its chemotherapeutic activity. In this study, we determined the chemotherapeutic activity of three RES esters that have been modified at the 4' hydroxyl by the addition of pivalate, butyrate, and isobutyrate. All of the RES derivatives disrupted the calcium signaling in prostate cancer cells more than the parent compound, RES. Further, we demonstrate that the RES derivatives may disrupt the calcium homeostasis by activating calcium release from the endoplasmic reticulum and inhibiting plasma membrane Ca²⁺-ATPase. The pivalated and butyrated RES derivatives decreased cell viability significantly more than RES. Because pivalated and butyrated RES are more effective than RES at targeting calcium signaling pathways, pivalated and butyrated RES may serve as more effective chemotherapeutics.

Keywords: 2-APB, 2-Aminoethyl diphenylborinate; AUC, area under the curve; BuRV, 4′-butyrate resveratrol; Calcium signaling; DMEM, Dulbecco's modified Eagle medium; DMSO, dimethyl sulfoxide; ER, endoplasmic reticulum; FBS, fetal bovine serum; Fura-2; Fura-2, Fura-2-Acetoxymethyl ester; HBSS, Ca2+- and Mg2+-free Hank's Balanced Salt Solution; IP3, inositol triphosphate; IP3R, inositol triphosphate receptor; IsoRV, 4′-isobutyrate resveratrol; MTT, 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; PBS, phosphate-buffered saline; PIP2, phosphatidylinositol biphosphate; PIV, 4′-pivalate resveratrol; PLC, phospholipase C; PMCA, plasma membrane Ca2+-ATPase; Plasma membrane Ca2+-ATPase; Prostate cancer; RES, resveratrol; Resveratrol; SERCA, sarcoendoplasmic reticular Ca2+-ATPase; TG, thapsigargin; [Ca2+]i, cytosolic calcium concentration.