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...
Saved in:
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2021-01-01
|
| Series: | PLoS ONE |
| Online Access: | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0254011&type=printable |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850239572716290048 |
|---|---|
| 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 |
| collection | DOAJ |
| 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 |
| id | doaj-art-37037cb7c95f4bc0aad71bf577eef502 |
| institution | OA Journals |
| issn | 1932-6203 |
| language | English |
| publishDate | 2021-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj-art-37037cb7c95f4bc0aad71bf577eef5022025-08-20T02:01:06ZengPublic Library of Science (PLoS)PLoS ONE1932-62032021-01-01167e025401110.1371/journal.pone.0254011Gemcitabine-induced Gli-dependent activation of hedgehog pathway resists to the treatment of urothelial carcinoma cells.Yu-Hao ChangHoi-Lam TamMeng-Chien LuHuei-Sheng HuangPatients 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.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0254011&type=printable |
| spellingShingle | 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. PLoS ONE |
| title | 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_short | 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 |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0254011&type=printable |
| work_keys_str_mv | AT yuhaochang gemcitabineinducedglidependentactivationofhedgehogpathwayresiststothetreatmentofurothelialcarcinomacells AT hoilamtam gemcitabineinducedglidependentactivationofhedgehogpathwayresiststothetreatmentofurothelialcarcinomacells AT mengchienlu gemcitabineinducedglidependentactivationofhedgehogpathwayresiststothetreatmentofurothelialcarcinomacells AT hueishenghuang gemcitabineinducedglidependentactivationofhedgehogpathwayresiststothetreatmentofurothelialcarcinomacells |