Cargando…

Thymoquinone affects the gemcitabine sensitivity of pancreatic cancer by regulating collagen via hypoxia inducible factor-1α

Objective: To clarify the potential therapeutic effects of thymoquinone (TQ) on pancreatic cancer and its gemcitabine (GEM) sensitivity. Methods: The expression levels of hypoxia inducible factor-1α (HIF-1α), collagens (COL1A1, COL3A1, and COL5A1), and transforming growth factor-β1 (TGFβ1) in pancre...

Descripción completa

Detalles Bibliográficos
Autores principales: Zhao, Zhanxue, Liu, Linxun, Chen, Hekai, Li, Shuai, Guo, Yan, Hou, Xiaofan, Yang, Jinyu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10264578/
https://www.ncbi.nlm.nih.gov/pubmed/37324458
http://dx.doi.org/10.3389/fphar.2023.1138265
_version_ 1785058352076685312
author Zhao, Zhanxue
Liu, Linxun
Chen, Hekai
Li, Shuai
Guo, Yan
Hou, Xiaofan
Yang, Jinyu
author_facet Zhao, Zhanxue
Liu, Linxun
Chen, Hekai
Li, Shuai
Guo, Yan
Hou, Xiaofan
Yang, Jinyu
author_sort Zhao, Zhanxue
collection PubMed
description Objective: To clarify the potential therapeutic effects of thymoquinone (TQ) on pancreatic cancer and its gemcitabine (GEM) sensitivity. Methods: The expression levels of hypoxia inducible factor-1α (HIF-1α), collagens (COL1A1, COL3A1, and COL5A1), and transforming growth factor-β1 (TGFβ1) in pancreatic cancer and para-carcinoma tissues were compared using immunohistochemical methods, and their relationships with TNM staging were analyzed. The effects of TQ on apoptosis, migration, invasion, and GEM sensitivity of pancreatic cancer cells were assessed using in vitro and in vivo experiments. Western blot and immunohistochemistry were used to detect the expression levels of HIF-1α, extracellular matrix (ECM) production pathway-related proteins, and TGFβ/Smad signaling pathway-related proteins. Results: The expression levels of HIF-1α, COL1A1, COL3A1, COL5A1, and TGFβ1 in pancreatic cancer tissues were significantly higher than those in para-carcinoma tissues and correlated with TNM staging (p < 0.05). TQ and GEM administration inhibited the migration and invasion of the human pancreatic cancer cell line PANC-1 and promoted the apoptosis of PANC-1 cells. The combination of TQ and GEM was more effective than GEM alone. Western blot analysis showed that the expression levels of HIF-1α, ECM production pathway-related proteins, and TGFβ/Smad signaling pathway-related proteins were significantly decreased when TQ was used to treat PANC-1 cells (p < 0.05), and the expression levels of these proteins in the TQ + GEM group were significantly more decreased than those in the GEM group. Overexpression or knockdown of HIF-1α in PANC-1 cells showed the same effects as those induced by TQ administration. In vivo experiments showed that in PANC-1 tumor-bearing mice, tumor volume and tumor weight in mice treated with GEM and TQ were significantly lower than those in control or GEM-treated mice, whereas cell apoptosis was significantly increased (p < 0.05). Western blot and immunohistochemistry results showed that the levels of HIF-1α, ECM production pathway-related proteins, and TGFβ/Smad signaling pathway-related proteins in the GEM + TQ treatment group were further decreased compared to the control group or the GEM treatment group (p < 0.05). Conclusion: In pancreatic cancer cells, TQ can promote apoptosis, inhibit migration, invasion, and metastasis, and enhance the sensitivity to GEM. The underlying mechanism may involve the regulation of ECM production through the TGFβ/Smad pathway, in which HIF-1α plays a key role.
format Online
Article
Text
id pubmed-10264578
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-102645782023-06-15 Thymoquinone affects the gemcitabine sensitivity of pancreatic cancer by regulating collagen via hypoxia inducible factor-1α Zhao, Zhanxue Liu, Linxun Chen, Hekai Li, Shuai Guo, Yan Hou, Xiaofan Yang, Jinyu Front Pharmacol Pharmacology Objective: To clarify the potential therapeutic effects of thymoquinone (TQ) on pancreatic cancer and its gemcitabine (GEM) sensitivity. Methods: The expression levels of hypoxia inducible factor-1α (HIF-1α), collagens (COL1A1, COL3A1, and COL5A1), and transforming growth factor-β1 (TGFβ1) in pancreatic cancer and para-carcinoma tissues were compared using immunohistochemical methods, and their relationships with TNM staging were analyzed. The effects of TQ on apoptosis, migration, invasion, and GEM sensitivity of pancreatic cancer cells were assessed using in vitro and in vivo experiments. Western blot and immunohistochemistry were used to detect the expression levels of HIF-1α, extracellular matrix (ECM) production pathway-related proteins, and TGFβ/Smad signaling pathway-related proteins. Results: The expression levels of HIF-1α, COL1A1, COL3A1, COL5A1, and TGFβ1 in pancreatic cancer tissues were significantly higher than those in para-carcinoma tissues and correlated with TNM staging (p < 0.05). TQ and GEM administration inhibited the migration and invasion of the human pancreatic cancer cell line PANC-1 and promoted the apoptosis of PANC-1 cells. The combination of TQ and GEM was more effective than GEM alone. Western blot analysis showed that the expression levels of HIF-1α, ECM production pathway-related proteins, and TGFβ/Smad signaling pathway-related proteins were significantly decreased when TQ was used to treat PANC-1 cells (p < 0.05), and the expression levels of these proteins in the TQ + GEM group were significantly more decreased than those in the GEM group. Overexpression or knockdown of HIF-1α in PANC-1 cells showed the same effects as those induced by TQ administration. In vivo experiments showed that in PANC-1 tumor-bearing mice, tumor volume and tumor weight in mice treated with GEM and TQ were significantly lower than those in control or GEM-treated mice, whereas cell apoptosis was significantly increased (p < 0.05). Western blot and immunohistochemistry results showed that the levels of HIF-1α, ECM production pathway-related proteins, and TGFβ/Smad signaling pathway-related proteins in the GEM + TQ treatment group were further decreased compared to the control group or the GEM treatment group (p < 0.05). Conclusion: In pancreatic cancer cells, TQ can promote apoptosis, inhibit migration, invasion, and metastasis, and enhance the sensitivity to GEM. The underlying mechanism may involve the regulation of ECM production through the TGFβ/Smad pathway, in which HIF-1α plays a key role. Frontiers Media S.A. 2023-05-31 /pmc/articles/PMC10264578/ /pubmed/37324458 http://dx.doi.org/10.3389/fphar.2023.1138265 Text en Copyright © 2023 Zhao, Liu, Chen, Li, Guo, Hou and Yang. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Zhao, Zhanxue
Liu, Linxun
Chen, Hekai
Li, Shuai
Guo, Yan
Hou, Xiaofan
Yang, Jinyu
Thymoquinone affects the gemcitabine sensitivity of pancreatic cancer by regulating collagen via hypoxia inducible factor-1α
title Thymoquinone affects the gemcitabine sensitivity of pancreatic cancer by regulating collagen via hypoxia inducible factor-1α
title_full Thymoquinone affects the gemcitabine sensitivity of pancreatic cancer by regulating collagen via hypoxia inducible factor-1α
title_fullStr Thymoquinone affects the gemcitabine sensitivity of pancreatic cancer by regulating collagen via hypoxia inducible factor-1α
title_full_unstemmed Thymoquinone affects the gemcitabine sensitivity of pancreatic cancer by regulating collagen via hypoxia inducible factor-1α
title_short Thymoquinone affects the gemcitabine sensitivity of pancreatic cancer by regulating collagen via hypoxia inducible factor-1α
title_sort thymoquinone affects the gemcitabine sensitivity of pancreatic cancer by regulating collagen via hypoxia inducible factor-1α
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10264578/
https://www.ncbi.nlm.nih.gov/pubmed/37324458
http://dx.doi.org/10.3389/fphar.2023.1138265
work_keys_str_mv AT zhaozhanxue thymoquinoneaffectsthegemcitabinesensitivityofpancreaticcancerbyregulatingcollagenviahypoxiainduciblefactor1a
AT liulinxun thymoquinoneaffectsthegemcitabinesensitivityofpancreaticcancerbyregulatingcollagenviahypoxiainduciblefactor1a
AT chenhekai thymoquinoneaffectsthegemcitabinesensitivityofpancreaticcancerbyregulatingcollagenviahypoxiainduciblefactor1a
AT lishuai thymoquinoneaffectsthegemcitabinesensitivityofpancreaticcancerbyregulatingcollagenviahypoxiainduciblefactor1a
AT guoyan thymoquinoneaffectsthegemcitabinesensitivityofpancreaticcancerbyregulatingcollagenviahypoxiainduciblefactor1a
AT houxiaofan thymoquinoneaffectsthegemcitabinesensitivityofpancreaticcancerbyregulatingcollagenviahypoxiainduciblefactor1a
AT yangjinyu thymoquinoneaffectsthegemcitabinesensitivityofpancreaticcancerbyregulatingcollagenviahypoxiainduciblefactor1a