title: Differential Redox Regulation of Ca²⁺ Signaling and Viability in Normal and Malignant Prostate Cells.
abstract: In prostate cancer, reactive oxygen species (ROS) are elevated and Ca(2+) signaling is impaired. Thus, several novel therapeutic strategies have been developed to target altered ROS and Ca(2+) signaling pathways in prostate cancer. Here, we investigate alterations of intracellular Ca(2+) and inhibition of cell viability caused by ROS in primary human prostate epithelial cells (hPECs) from healthy tissue and prostate cancer cell lines (LNCaP, DU145, and PC3). In hPECs, LNCaP and DU145 H2O2 induces an initial Ca(2+) increase, which in prostate cancer cells is blocked at high concentrations of H2O2. Upon depletion of intracellular Ca(2+) stores, store-operated Ca(2+) entry (SOCE) is activated. SOCE channels can be formed by hexameric Orai1 channels; however, Orai1 can form heteromultimers with its homolog, Orai3. Since the redox sensor of Orai1 (Cys-195) is absent in Orai3, the Orai1/Orai3 ratio in T cells determines the redox sensitivity of SOCE and cell viability. In prostate cancer cells, SOCE is blocked at lower concentrations of H2O2 compared with hPECs. An analysis of data from hPECs, LNCaP, DU145, and PC3, as well as previously published data from naive and effector TH cells, demonstrates a strong correlation between the Orai1/Orai3 ratio and the SOCE redox sensitivity and cell viability. Therefore, our data support the concept that store-operated Ca(2+) channels in hPECs and prostate cancer cells are heteromeric Orai1/Orai3 channels with an increased Orai1/Orai3 ratio in cells derived from prostate cancer tumors. In addition, ROS-induced alterations in Ca(2+) signaling in prostate cancer cells may contribute to the higher sensitivity of these cells to ROS.
authors.affiliation: Biophysics, Center for Integrated Physiology and Molecular Medicine, School of Medicine, Saarland University, Homburg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Holzmann
authors.affiliation: Biophysics, Center for Integrated Physiology and Molecular Medicine, School of Medicine, Saarland University, Homburg, Germany; Center of Human and Molecular Biology, Saarland University, Homburg, Germany.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Kilch
authors.affiliation: Biophysics, Center for Integrated Physiology and Molecular Medicine, School of Medicine, Saarland University, Homburg, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Kappel
authors.affiliation: Biophysics, Center for Integrated Physiology and Molecular Medicine, School of Medicine, Saarland University, Homburg, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Dörr
authors.affiliation: Clinics of Urology and Pediatric Urology, Saarland University, Homburg, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Jung
authors.affiliation: Clinics of Urology and Pediatric Urology, Saarland University, Homburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Stöckle
authors.affiliation: Biophysics, Center for Integrated Physiology and Molecular Medicine, School of Medicine, Saarland University, Homburg, Germany.
authors.forename: Ivan
authors.initials: I
authors.lastname: Bogeski
authors.affiliation: Biophysics, Center for Integrated Physiology and Molecular Medicine, School of Medicine, Saarland University, Homburg, Germany; Center of Human and Molecular Biology, Saarland University, Homburg, Germany. Electronic address: bpcpei@uks.eu.
authors.forename: Christine
authors.initials: C
authors.lastname: Peinelt
mesh_terms: D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D004847:Epithelial Cells / Q000502:physiology*; D055785:Gene Knockdown Techniques; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism* / Q000633:toxicity; D042541:Intracellular Space / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D000071740:ORAI1 Protein; D010084:Oxidation-Reduction; D018408:Patch-Clamp Techniques; D011467:Prostate / Q000502:physiology*; D011471:Prostatic Neoplasms / Q000503:physiopathology*; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D000071737:Stromal Interaction Molecule 1
chemical_list: D015220:Calcium Channels; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D000071740:ORAI1 Protein; C510746:ORAI1 protein, human; C522867:Orai3 protein, human; D017382:Reactive Oxygen Species; C103530:STIM1 protein, human; D000071737:Stromal Interaction Molecule 1; D006861:Hydrogen Peroxide; D002118:Calcium