© 2022, The Author(s), under exclusive licence to Springer Nature B.V.Background: Today, androgen receptor (AR)-mediated signaling mechanisms in prostate cancer are intensively studied. However, the roles of other steroid hormones in prostate cancer and their effects on androgenic signaling still remain a mystery. Recent studies focused on the androgen-mediated regulation of protein quality control mechanisms such as endoplasmic reticulum-associated degradation (ERAD) and unfolded protein response (UPR) in prostate cancer cells. Present study, we investigated the action of progesterone signaling on ERAD and UPR mechanisms and analyzed the crosstalk of progesterone signaling with androgenic signal in prostate cancer cells. Methods and results: The mode of action of progesterone on ERAD, UPR and AR signaling in prostate cancer was investigated by cell culture studies using LNCaP and 22Rv1 cells. To this aim qRT-PCR, western-blotting assay, immunofluorescent microscopy, nuclear fractionation and bioinformatic analysis were used. Our results indicated that progesterone positively regulates mRNA and protein levels of ERAD components in LNCaP cells. Also, it induced the IRE⍺ and PERK branches of UPR signaling. Progesterone receptor antagonist effectively antagonized the progesterone-induced responses. We also had similar results in 22Rv1 cells. Also, we tested the effect of the pharmacologically reducing of IRE⍺ and PERK signaling on progesterone-induced ERAD. Additionally, we determined the presence of putative progesterone response elements (PREs) in the promoter regions of ERAD members by bioinformatic tool. More strikingly, we found progesterone regulates AR signaling by modulating the nuclear transactivation of AR. Conclusion: Herein, we defined that progesterone hormone positively regulates ERAD and UPR mechanisms in prostate cancer cells and that progesterone contributes to the molecular biology of prostate cancer by regulating androgenic signaling. Graphical abstract: Mode of Action of Progesteron on Androgen sensitive prostate cancer cells. [Figure not available: see fulltext.]