Basic Study
Copyright ©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jun 7, 2024; 30(21): 2793-2816
Published online Jun 7, 2024. doi: 10.3748/wjg.v30.i21.2793
Thymoquinone affects hypoxia-inducible factor-1α expression in pancreatic cancer cells via HSP90 and PI3K/AKT/mTOR pathways
Zhan-Xue Zhao, Shuai Li, Lin-Xun Liu
Zhan-Xue Zhao, Lin-Xun Liu, Department of General Surgery, Qinghai Provincial People's Hospital, Xining 810007, Qinghai Province, China
Shuai Li, Department of Clinical Pharmacy, The Affiliated Hospital of Qinghai University, Xining 810001, Qinghai Province, China
Author contributions: Zhao ZX and Li S performed the experiments, acquired and analyzed data, write the manuscript; Liu LX participated in article review and financial support; Zhao ZX and Li S contribute equally. All authors have read and approved the final manuscript.
Supported by Health Commission of Qinghai Province, No. 2021-wjzdx-18.
Institutional review board statement: The study was reviewed and approved by the Ethics Committee of Qinghai Provincial People's Hospital, No. 2021-106.
Institutional animal care and use committee statement: This study does not involve animal research.
Conflict-of-interest statement: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Data sharing statement: Technical appendix, statistical code, and dataset available from the corresponding author at zhaozhanxue1025@sina.com.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Lin-Xun Liu, MD, Chief Physician, Department of General Surgery, Qinghai Provincial People's Hospital, No. 2 Gonghe Road, Chengdong District, Xining 810007, Qinghai Province, China. 147599835@qq.com
Received: November 12, 2023
Revised: April 14, 2024
Accepted: May 8, 2024
Published online: June 7, 2024
Processing time: 203 Days and 16.6 Hours
Abstract
BACKGROUND

Pancreatic cancer (PC) is associated with some of the worst prognoses of all major cancers. Thymoquinone (TQ) has a long history in traditional medical practice and is known for its anti-cancer, anti-inflammatory, anti-fibrosis and antioxidant pharmacological activities. Recent studies on hypoxia-inducible factor-1α (HIF-1α) and PC have shown that HIF-1α affects the occurrence and development of PC in many aspects. In addition, TQ could inhibit the development of renal cancer by decreasing the expression of HIF-1α. Therefore, we speculate whether TQ affects HIF-1α expression in PC cells and explore the mechanism.

AIM

To elucidate the effect of TQ in PC cells and the regulatory mechanism of HIF-1α expression.

METHODS

Cell counting kit-8 assay, Transwell assay and flow cytometry were performed to detect the effects of TQ on the proliferative activity, migration and invasion ability and apoptosis of PANC-1 cells and normal pancreatic duct epithelial (hTERT-HPNE) cells. Quantitative real-time polymerase chain reaction and western blot assay were performed to detect the expression of HIF-1α mRNA and protein in PC cells. The effects of TQ on the HIF-1α protein initial expression pathway and ubiquitination degradation in PANC-1 cells were examined by western blot assay and co-immunoprecipitation.

RESULTS

TQ significantly inhibited proliferative activity, migration, and invasion ability and promoted apoptosis of PANC-1 cells; however, no significant effects on hTERT-HPNE cells were observed. TQ significantly reduced the mRNA and protein expression levels of HIF-1α in PANC-1, AsPC-1, and BxPC-3 cells. TQ significantly inhibited the expression of the HIF-1α initial expression pathway (PI3K/AKT/mTOR) related proteins, and promoted the ubiquitination degradation of the HIF-1α protein in PANC-1 cells. TQ had no effect on the hydroxylation and von Hippel Lindau protein mediated ubiquitination degradation of the HIF-1α protein but affected the stability of the HIF-1α protein by inhibiting the interaction between HIF-1α and HSP90, thus promoting its ubiquitination degradation.

CONCLUSION

The regulatory mechanism of TQ on HIF-1α protein expression in PC cells was mainly to promote the ubiquitination degradation of the HIF-1α protein by inhibiting the interaction between HIF-1α and HSP90; Secondly, TQ reduced the initial expression of HIF-1α protein by inhibiting the PI3K/AKT/mTOR pathway.

Keywords: Thymoquinone; Pancreatic cancer; Hypoxia-inducible factor-1α; PI3K/AKT/mTOR; HSP90

Core Tip: Thymoquinone (TQ) could significantly inhibit the proliferative activity, invasion and migration ability and promote the apoptosis of pancreatic cancer (PC) cells. TQ could inhibit hypoxia-inducible factor-1α (HIF-1α) expression in PC cells. The mechanism of TQ on HIF-1α protein expression in PC cells was to promote the ubiquitination degradation of HIF-1α protein by inhibiting the interaction between HIF-1α and HSP90 and reduce the initial expression of HIF-1α protein by inhibiting the PI3K/AKT/mTOR pathway.