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

Abstract 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 t...

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Autores principales:	Diana Trnski, Maja Sabol, Sanja Tomić, Ivan Štefanac, Milanka Mrčela, Vesna Musani, Nikolina Rinčić, Matea Kurtović, Tina Petrić, Sonja Levanat, Petar Ozretić
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/a35aa281398c4fa6bbbb5775d4883d32
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spelling	oai:doaj.org-article:a35aa281398c4fa6bbbb5775d4883d322021-12-02T17:56:56ZSHH-N non-canonically sustains androgen receptor activity in androgen-independent prostate cancer cells10.1038/s41598-021-93971-62045-2322https://doaj.org/article/a35aa281398c4fa6bbbb5775d4883d322021-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-93971-6https://doaj.org/toc/2045-2322Abstract 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.Diana TrnskiMaja SabolSanja TomićIvan ŠtefanacMilanka MrčelaVesna MusaniNikolina RinčićMatea KurtovićTina PetrićSonja LevanatPetar OzretićNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Diana Trnski Maja Sabol Sanja Tomić Ivan Štefanac Milanka Mrčela Vesna Musani Nikolina Rinčić Matea Kurtović Tina Petrić Sonja Levanat Petar Ozretić SHH-N non-canonically sustains androgen receptor activity in androgen-independent prostate cancer cells
description	Abstract 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.
format	article
author	Diana Trnski Maja Sabol Sanja Tomić Ivan Štefanac Milanka Mrčela Vesna Musani Nikolina Rinčić Matea Kurtović Tina Petrić Sonja Levanat Petar Ozretić
author_facet	Diana Trnski Maja Sabol Sanja Tomić Ivan Štefanac Milanka Mrčela Vesna Musani Nikolina Rinčić Matea Kurtović Tina Petrić Sonja Levanat Petar Ozretić
author_sort	Diana Trnski
title	SHH-N non-canonically sustains androgen receptor activity in androgen-independent prostate cancer cells
title_short	SHH-N non-canonically sustains androgen receptor activity in androgen-independent prostate cancer cells
title_full	SHH-N non-canonically sustains androgen receptor activity in androgen-independent prostate cancer cells
title_fullStr	SHH-N non-canonically sustains androgen receptor activity in androgen-independent prostate cancer cells
title_full_unstemmed	SHH-N non-canonically sustains androgen receptor activity in androgen-independent prostate cancer cells
title_sort	shh-n non-canonically sustains androgen receptor activity in androgen-independent prostate cancer cells
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/a35aa281398c4fa6bbbb5775d4883d32
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SHH-N non-canonically sustains androgen receptor activity in androgen-independent prostate cancer cells

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