Abstract
•In prostate cancer cells membrane androgen receptor (mAR) activation increases pH.•mAR activation upregulates cariporide sensitive Na+/H+ exchanger (NHE).•The effect of mAR on pH and NHE requires serum & glucocorticoid inducible kinase.•The effect of mAR on pH and NHE requires Rho-associated protein kinase.
Membrane androgen receptors (mAR) are expressed in several tumors. mAR activation by testosterone albumin conjugates (TAC) suppresses tumor growth and migration. mAR signaling involves phosphoinositide-3-kinase (PI3K) and Rho-associated protein kinase (ROCK). PI3K stimulates serum- and glucocorticoid-inducible kinase SGK1, which in turn activates Na+/H+-exchangers (NHE). In prostate cancer cells cytosolic pH (pHi) was determined utilizing 2′,7′-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein-fluorescence and NHE-activity utilizing Na+-dependent cytosolic realkalinization following an ammonium pulse. TAC (100nM) significantly increased pHi and NHE-activity, effects abrogated by NHE1-inhibitor cariporide (10μM), SGK1-inhibitors EMD638683 (50μM) and GSK650349 (10μM) and ROCK-inhibitors Y-27632 (10μM) and fasudil (100μM). TAC treatment rapidly and significantly increased cell volume and actin polymerization, effects abolished in the presence of cariporide. Thus, mAR-activation activates cariporide-sensitive Na+/H+-exchangers, an effect requiring SGK1 and ROCK activity.