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Progesterone regulates the endoplasmic reticulum-associated degradation and Unfolded Protein Response axis by mimicking the androgenic stimulation in prostate cancer cells

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Abstract

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.

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Data availability

The data generated in this study are available upon request from the corresponding author.

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Acknowledgements

We thank Dr. Fahri Saatcioglu (Department of Biosciences, University of Oslo, Norway) for the Human prostate adenocarcinoma cell lines, LNCaP and Du145 and synthetic androgen R1881. We thank Suleyman Demirel University-Innovative Technologies Application and Research Center. Fluorescence microscopic examination was performed at Mehmet Akif Ersoy University, Veterinary Faculty, Department of Pathology, we thank Dr. Ozlem OZMEN.

Funding

This work received support from Süleyman Demirel Üniversitesi, (Grant Numbers TSG-2021-8302, TAB-2020-8253).

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Authors and Affiliations

  1. Department of Biochemistry, Faculty of Pharmacy, Suleyman Demirel University, 32260, Isparta, Turkey

    Yalcin Erzurumlu

  2. Department of Bioengineering, Institute of Science, Suleyman Demirel University, 32260, Isparta, Turkey

    Hatice Kubra Dogan

  3. Department of Pharmacology, Faculty of Medicine, Suleyman Demirel University, 32260, Isparta, Turkey

    Deniz Catakli

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  1. Yalcin Erzurumlu
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Contributions

YE initiated and directed the project, designed, and conducted the experiments, analyzed, and interpreted the results, and wrote the manuscript. HKD and DC assisted experimental studies. All correspondence and requests for materials should be addressed to YE. All authors have read and approved the final version of the article.

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Correspondence to Yalcin Erzurumlu.

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Erzurumlu, Y., Dogan, H.K. & Catakli, D. Progesterone regulates the endoplasmic reticulum-associated degradation and Unfolded Protein Response axis by mimicking the androgenic stimulation in prostate cancer cells. Mol Biol Rep 50, 1253–1265 (2023). https://doi.org/10.1007/s11033-022-08065-x

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