The tumorigenic properties of prostate cancer are regulated by advanced hormonal regulation‐mediated complex molecular signals. Therefore, characterizing the regulation of these signal transduction systems is crucial for understanding prostate cancer biology. Recent studies have shown that endoplasmic reticulum (ER)‐localized protein quality control mechanisms, including ER‐associated degradation (ERAD) and unfolded protein response (UPR) signaling contribute to prostate carcinogenesis and to the development of drug resistance. It has also been determined that these systems are tightly regulated by androgens. However, the role of estrogenic signaling in prostate cancer and its effects on protein quality control mechanisms is not fully understood. Herein, we investigated the regulatory effects of estrogens on ERAD and UPR and their impacts on prostate carcinogenesis. We found that estrogens strongly regulated the ERAD components and IRE1⍺ branch of UPR by Er⍺/β/AR axis. Besides, estrogenic signaling rigorously regulated the tumorigenicity of prostate cancer cells by promoting c‐Myc expression and epithelial‐mesenchymal transition (EMT). Moreover, estrogenic signal blockage significantly decreased the tumorigenic features of prostate cancer cells. Additionally, simultaneous inhibition of androgenic/estrogenic signals more efficiently inhibited tumorigenicity of prostate cancer cells, including proliferation, migration, invasion and colonial growth. Furthermore, computational‐based molecular docking, molecular dynamics simulations and MMPBSA calculations supported the estrogenic stimulation of AR. Present findings suggested that ERAD components and IRE1⍺ signaling are tightly regulated by estrogen‐stimulated AR and Er⍺/β. Our data suggest that treatment approaches targeting the co‐inhibition of androgenic/estrogenic signals may pave the way for new treatment approaches to be developed for prostate cancer.
Objective: Tamoxifen is the most widely used therapeutic agent for the treatment of ER α-positive breast cancer. However, the development of resistance to tamoxifen in the majority of patients limits the therapeutic efficacy of tamoxifen and reduces the survival rate of patients. Ca+2 signaling mechanism, which has many critical roles including cell motility and gene expression regulation, has important roles in processes such as proliferation, migration, angiogenesis, and drug resistance development related to carcinogenesis. In this study, we aimed to investigate the effect of Calcium ionophore A23187 (calcimicin), which has high Ca+2 selectivity and mediates Ca+2 output from the endoplasmic reticulum, on proliferation and tamoxifen resistance in tamoxifen-resistant breast cancer cells.
Materials and Methods: WST-1-based cell proliferation analyzes were performed to evaluate the effect of A23187 or Tamoxifen and A23187 combined treatment on cell proliferation in Tamoxifen-resistant breast cancer cells MCF-7/TAMR-1. In addition, microscopic examinations were performed and photographed.
Results: A21387 has an antiproliferative effect on MCF-7/TAMR-1 cells. Moreover, a combined treatment of A23187 and tamoxifen synergistically reduced the proliferative capacity of cells manner dose-dependent by limiting tamoxifen resistance.
Conclusion: Our findings suggest that modulation of calcium signaling by A23187 may be a promising approach to improve tamoxifen sensitivity in breast cancer cells.
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