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.

Crosstalk between calcium and reactive oxygen species signaling in cancer

“…Clearly, the source of ROS, levels and duration of this redox signal will determine the eventual impact on SOCE. For example, domains of localized ROS production at the ER and mitochondria may exclusively affect SOCE via redox activation of STIM1 and hence lead to pro-tumorigenic Ca 2+ signaling, while exogenous redox stress sensed by plasma membrane localized ORAI channels may block SOCE and attenuate proliferation of tumor cells and also make tumor cells more susceptible to redox stress (Figure 7) [198]. It is also possible that ROS mediate STIM translocation and SOCE activation indirectly, through redox activation of ER Ca 2+ regulators IP 3 R and SERCA, which are also redox sensitive (See section 4).…”

“…It was shown that prostate cancer cell lines have a higher ratio of ORAI1/ORAI3 compared to primary human prostate epithelial cells [198]. The authors went on to show that an increased ORAI1/ORAI3 ratio makes prostate cancer cells more redox sensitive to SOCE inactivation by H 2 O 2 [198].…”

“…It was shown that prostate cancer cell lines have a higher ratio of ORAI1/ORAI3 compared to primary human prostate epithelial cells [198]. The authors went on to show that an increased ORAI1/ORAI3 ratio makes prostate cancer cells more redox sensitive to SOCE inactivation by H 2 O 2 [198]. H 2 O 2 exposure of prostate cancer cells and normal prostate epithelial cells led to an initial increase in cytosolic Ca 2+ , likely as a consequence of ROS-dependent TRP channel activation, which differed between cancer and normal cells.…”

“…The prostate cancer cell line LNCaP displaying a 10 fold lower H 2 O 2 IC 50 value compared to the normal prostate epithelial cell line hPECs. Although the prostate cancer cell DU145 displayed a similar IC 50 to hPECs, the authors correlated a change in the ORAI1/ORAI3 expression ratio to increased susceptibility of cells to redox stress [198]. As mentioned previously, tumor cells are often more susceptible to ROS toxicity, This phenotype may be due to some tumor cells having higher intracellular steady state levels of ROS, which in turn places cells closer to the cytotoxic threshold of ROS, an observation that has triggered research into utilizing ROS-agents for chemotherapeutic applications [79-82, 99].…”

“…Holzmann et al . proposed that ROS-mediated inactivation of ORAI1 may also contribute to higher sensitivity of prostate cancer cells to ROS, due to dampening of SOCE dependent pro-proliferative Ca 2+ signaling [198, 230]. The authors proposed that this altered ORAI1/ORAI3 expression ratio could provide a therapeutic opportunity to target the pro-proliferative actions of SOCE by carefully tuning redox-mediated inactivation to only affect tumor cells [198].…”