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SHH-N non-canonically sustains androgen receptor activity in androgen-independent prostate cancer cells

Trnski, Diana; Sabol, Maja; Tomić, Sanja; Štefanac, Ivan; Mrčela, Milanka; Musani, Vesna; Rinčić, Nikolina; Kurtović, Matea; Petrić, Tina; Levanat, Sonja; Ozretić, Petar (2021) SHH-N non-canonically sustains androgen receptor activity in androgen-independent prostate cancer cells. Scientific reports, 11 (1). ISSN 2045-2322

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Prostate cancer is the second most frequent cancer diagnosed in men worldwide. Localized disease can be successfully treated, but advanced cases are more problematic. After initial effectiveness of androgen deprivation therapy, resistance quickly occurs. Therefore, we aimed to investigate the role of Hedgehog-GLI (HH-GLI) signaling in sustaining androgen-independent growth of prostate cancer cells. We found various modes of HH-GLI signaling activation in prostate cancer cells depending on androgen availability. When androgen was not deprived, we found evidence of non-canonical SMO signaling through the SRC kinase. After short-term androgen deprivation canonical HH-GLI signaling was activated, but we found little evidence of canonical HH-GLI signaling activity in androgen-independent prostate cancer cells. We show that in androgen-independent cells the pathway ligand, SHH-N, non-canonically binds to the androgen receptor through its cholesterol modification. Inhibition of this interaction leads to androgen receptor signaling downregulation. This implies that SHH-N activates the androgen receptor and sustains androgen-independence. Targeting this interaction might prove to be a valuable strategy for advanced prostate cancer treatment. Also, other non-canonical aspects of this signaling pathway should be investigated in more detail and considered when developing potential therapies.

Item Type: Article
Uncontrolled Keywords: prostate cancer ; HH-GLI signaling ; SHH-N ; androgen receptor
Subjects: NATURAL SCIENCES > Biology
Divisions: Division of Molecular Medicine
Division of Organic Chemistry and Biochemistry
Project titleProject leaderProject codeProject type
Biološka važnost dipeptidil peptidaze III i njezin utjecaj na zdravlje čovjekaTomić, SanjaIP-2018-01-2936HRZZ
Regulacija GLI koda u tumorima ovisnim o BRAF/NRAS mutacijamaSabol, MajaIP-2018-01-4889HRZZ
Depositing User: Sofija Konjević
Date Deposited: 06 Aug 2021 09:34
DOI: 10.1038/s41598-021-93971-6

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