Effects of timolol on Ca2+ handling and viability in human prostate cancer cells |
| |
Authors: | Jue-Long Wang Chiang-Ting Chou Wei-Zhe Liang Cherng-Jer Wu Chun-Chi Kuo |
| |
Institution: | 1. Department of Rehabilitation, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan;2. Department of Nursing, Division of Basic Medical Sciences, Chang Gung University of Science and Technology, Chia-Yi, Taiwan;3. Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan;4. Department of Pharmacy, Tajen University, Pingtung, Taiwan;5. Yuh-Ing Junior College of Health Care &6. Management, Kaohsiung, Taiwan;7. Department of Pharmacy, Kaohsiung Veterans General Hospital Pingtung Branch, Pingtung, Taiwan;8. Department of Nursing, Tzu Hui Institute of Technology, Pingtung, Taiwan |
| |
Abstract: | Timolol is a medication used widely to treat glaucoma. Regarding Ca2+ signaling, timolol was shown to modulate Ca2+-related physiology in various cell types, however, the effect of timolol on Ca2+ homeostasis and cell viability has not been explored in human prostate cancer cells. The aim of this study was to explore the effect of timolol on intracellular Ca2+ concentrations (Ca2+]i) and viability in PC3 human prostate cancer cells. Timolol at concentrations of 100–1000?μM induced Ca2+]i rises. The Ca2+ signal in Ca2+-containing medium was reduced by removal of extracellular Ca2+ by approximately 75%. Timolol (1000?μM) induced Mn2+ influx suggesting of Ca2+ entry. Timolol-induced Ca2+ entry was partially inhibited by three inhibitors of store-operated Ca2+ channels: nifedipine, econoazole and SKF96365, and by a protein kinase C (PKC) activator (phorbol 12-myristate 13 acetate PMA]) or an inhibitor (GF109203X). In Ca2+-free medium, treatment with the endoplasmic reticulum Ca2+ pump inhibitor thapsigargin abolished timolol-evoked Ca2+]i rises. Conversely, treatment with timolol abolished thapsigargin-evoked Ca2+]i rises. Inhibition of phospholipase C (PLC) with U73122 abolished timolol-induced Ca2+]i rises. Timolol at concentrations between 200 and 600?μM killed cells in a concentration-dependent fashion. Chelation of cytosolic Ca2+ with 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid/AM (BAPTA/AM) did not reverse cytotoxicity of timolol. Together, in PC3 cells, timolol induced Ca2+]i rises by evoking Ca2+release from the endoplasmic reticulum in a PLC-dependent manner, and Ca2+ influx via PKC-regulated store-operated Ca2+ entry. Timolol also caused cell death that was not linked to preceding Ca2+]i rises. |
| |
Keywords: | Ca2+ timolol endoplasmic reticulum human prostate cancer cells viability |
|
|