1,25(OH)2 D3 induced vitamin D receptor signaling negatively regulates endoplasmic reticulum-associated degradation (ERAD) and androgen receptor signaling in human prostate cancer cells

• Published in: Cellular signalling 2023-03, Vol.103, p.110577, Article 110577
• Main Authors: Erzurumlu, Yalcin, Aydogdu, Esra, Dogan, Hatice Kubra, Catakli, Deniz, Muhammed, Muhammed Tilahun, Buyuksandic, Buket
• Format: Article
• Language: English
• Subjects: 1,25(OH)2 D3; Androgen receptor; Endoplasmic reticulum-associated degradation; Prostate cancer; Unfolded protein response; Vitamin D receptor
• ISSN: 0898-6568; 1873-3913
• DOI: 10.1016/j.cellsig.2022.110577

Steroid hormone signaling is critical in the tumor progression and the regulation of physiological mechanisms such as endoplasmic reticulum-associated degradation (ERAD) and unfolded protein response (UPR) in prostate cancer. 1,25(OH)2 D3 is an active metabolite of vitamin D classified as a steroid hormone. It exhibits anti-tumor effects, including angiogenesis and suppression of cell cycle progression. Moreover, progressively reducing expression levels of vitamin D receptor (VDR) are observed in many cancer types, including the prostate. In the present study, we investigated the molecular action of 1,25(OH)2 D3 on ERAD, UPR and androgenic signaling. We found that 1,25(OH)2 D3 negatively regulated the expression level of ERAD components and divergently controlled the inositol-requiring enzyme 1⍺ (IRE1⍺) and protein kinase RNA-like ER kinase (PERK) branches of UPR in LNCaP human prostate cancer cells. Also, similar results were obtained with another human prostate cancer cell line, 22Rv1. More strikingly, we found that androgenic signaling is negatively regulated by VDR signaling. Also, molecular docking supported the inhibitory effect of 1,25(OH)2 D3 on AR signaling. Moreover, we found VDR signaling suppressed tumor progression by decreasing c-Myc expression and reducing the epithelial-mesenchymal transition (EMT). Additionally, 1,25(OH)2 D3 treatment significantly inhibited the 3D-tumor formation of LNCaP cells. Our results suggest that further molecular characterization of the action of VDR signaling in other cancer types such as estrogenic signal in breast cancer will provide important contributions to a better understanding of the roles of steroid hormone receptors in carcinogenesis processes. Schematic representation of 1,25(OH)2 D3 -induced signaling on ERAD and UPR axis in androgen-dependent prostate cancer and interaction model of 1,25(OH)2 D3 with AR. [Display omitted] •1,25(OH)2 D3 negatively regulates the expression level of ERAD components except for SVIP which is an endogenous ERAD inhibitor protein.•1,25(OH)2 D3 divergently coordinates the branches of UPR signaling in prostate cancer cells.•mRNA and protein levels of AR are tightly regulated by VDR signaling.•Molecular docking study indicated that 1,25(OH)2 D3 could inhibit the AR with a mechanism similar to bicalutamide.