Gemcitabine-induced Gli-dependent activation of hedgehog pathway resists to the treatment of urothelial carcinoma cells.

Patients with urothelial carcinoma (UC) experience gemcitabine resistance is a critical issue. The role of hedgehog pathway in the problem was explored. The expressions of phospho-AKTser473, phospho-GSK3βser9 and Gli2 were up-regulated in gemcitabine-resistant NTUB1 (NGR) cells. Without hedgehog lig...

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Autores principales:	Yu-Hao Chang, Hoi-Lam Tam, Meng-Chien Lu, Huei-Sheng Huang
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/37037cb7c95f4bc0aad71bf577eef502
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id	oai:doaj.org-article:37037cb7c95f4bc0aad71bf577eef502
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spelling	oai:doaj.org-article:37037cb7c95f4bc0aad71bf577eef5022021-12-02T20:09:36ZGemcitabine-induced Gli-dependent activation of hedgehog pathway resists to the treatment of urothelial carcinoma cells.1932-620310.1371/journal.pone.0254011https://doaj.org/article/37037cb7c95f4bc0aad71bf577eef5022021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0254011https://doaj.org/toc/1932-6203Patients with urothelial carcinoma (UC) experience gemcitabine resistance is a critical issue. The role of hedgehog pathway in the problem was explored. The expressions of phospho-AKTser473, phospho-GSK3βser9 and Gli2 were up-regulated in gemcitabine-resistant NTUB1 (NGR) cells. Without hedgehog ligands, Gli proteins can be phosphorylated by GSK3β kinase to inhibit their downstream regulations. Furthermore, the GSK3β kinase can be phosphorylated by AKT at its Ser9 residue to become an inactive kinase. Therefore, overexpression of AKT1, Flag-GSKS9D (constitutively inactive form) or active Gli2 (GLI2ΔN) in NTUB1 cells could activate Gli2 pathway to enhance migration/invasion ability and increase gemcitabine resistance, respectively. Conversely, overexpression of Flag-GSKS9A (constitutively active form) or knockdown of Gli2 could suppress Gli2 pathway, and then reduce gemcitabine resistance in NGR cells. Therefore, we suggest gemcitabine-activated AKT/GSK3β pathway can elicit Gli2 activity, which leads to enhanced migration/invasion ability and resistance to gemcitabine therapy in UC patients. The non-canonical hedgehog pathway should be evaluated in the therapy to benefit UC patients.Yu-Hao ChangHoi-Lam TamMeng-Chien LuHuei-Sheng HuangPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 7, p e0254011 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Yu-Hao Chang Hoi-Lam Tam Meng-Chien Lu Huei-Sheng Huang Gemcitabine-induced Gli-dependent activation of hedgehog pathway resists to the treatment of urothelial carcinoma cells.
description	Patients with urothelial carcinoma (UC) experience gemcitabine resistance is a critical issue. The role of hedgehog pathway in the problem was explored. The expressions of phospho-AKTser473, phospho-GSK3βser9 and Gli2 were up-regulated in gemcitabine-resistant NTUB1 (NGR) cells. Without hedgehog ligands, Gli proteins can be phosphorylated by GSK3β kinase to inhibit their downstream regulations. Furthermore, the GSK3β kinase can be phosphorylated by AKT at its Ser9 residue to become an inactive kinase. Therefore, overexpression of AKT1, Flag-GSKS9D (constitutively inactive form) or active Gli2 (GLI2ΔN) in NTUB1 cells could activate Gli2 pathway to enhance migration/invasion ability and increase gemcitabine resistance, respectively. Conversely, overexpression of Flag-GSKS9A (constitutively active form) or knockdown of Gli2 could suppress Gli2 pathway, and then reduce gemcitabine resistance in NGR cells. Therefore, we suggest gemcitabine-activated AKT/GSK3β pathway can elicit Gli2 activity, which leads to enhanced migration/invasion ability and resistance to gemcitabine therapy in UC patients. The non-canonical hedgehog pathway should be evaluated in the therapy to benefit UC patients.
format	article
author	Yu-Hao Chang Hoi-Lam Tam Meng-Chien Lu Huei-Sheng Huang
author_facet	Yu-Hao Chang Hoi-Lam Tam Meng-Chien Lu Huei-Sheng Huang
author_sort	Yu-Hao Chang
title	Gemcitabine-induced Gli-dependent activation of hedgehog pathway resists to the treatment of urothelial carcinoma cells.
title_short	Gemcitabine-induced Gli-dependent activation of hedgehog pathway resists to the treatment of urothelial carcinoma cells.
title_full	Gemcitabine-induced Gli-dependent activation of hedgehog pathway resists to the treatment of urothelial carcinoma cells.
title_fullStr	Gemcitabine-induced Gli-dependent activation of hedgehog pathway resists to the treatment of urothelial carcinoma cells.
title_full_unstemmed	Gemcitabine-induced Gli-dependent activation of hedgehog pathway resists to the treatment of urothelial carcinoma cells.
title_sort	gemcitabine-induced gli-dependent activation of hedgehog pathway resists to the treatment of urothelial carcinoma cells.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/37037cb7c95f4bc0aad71bf577eef502
work_keys_str_mv	AT yuhaochang gemcitabineinducedglidependentactivationofhedgehogpathwayresiststothetreatmentofurothelialcarcinomacells AT hoilamtam gemcitabineinducedglidependentactivationofhedgehogpathwayresiststothetreatmentofurothelialcarcinomacells AT mengchienlu gemcitabineinducedglidependentactivationofhedgehogpathwayresiststothetreatmentofurothelialcarcinomacells AT hueishenghuang gemcitabineinducedglidependentactivationofhedgehogpathwayresiststothetreatmentofurothelialcarcinomacells
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Gemcitabine-induced Gli-dependent activation of hedgehog pathway resists to the treatment of urothelial carcinoma cells.

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