Meloxicam, a Selective COX-2 Inhibitor, Mediates Hypoxia-Inducible Factor- (HIF-) 1 α Signaling in Hepatocellular Carcinoma.

Autor: Zhou Y; School of Medicine and Life Sciences, University of Jinan-Shandong Academy of Medical Sciences, Jinan 250200, China.; Department of Hepatobiliary Surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, China., Dong X; Department of Hepatobiliary and Pancreatic Surgery Breast and Thyroid Surgery, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning 530021, China., Xiu P; Department of Hepatobiliary Surgery, Shandong Provincial Qianfoshan Hospital, The First Hospital Affiliated with Shandong First Medical University, Jinan 250014, China., Wang X; Department of Hepatobiliary Surgery, Shandong Provincial Qianfoshan Hospital, The First Hospital Affiliated with Shandong First Medical University, Jinan 250014, China., Yang J; Department of Hepatobiliary and Pancreatic Surgery Breast and Thyroid Surgery, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning 530021, China., Li L; Department of Hepatobiliary Surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, China., Li Z; Department of Hepatobiliary Surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, China., Sun P; Department of Hepatobiliary Surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, China., Shi X; Department of Hepatobiliary Surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, China., Zhong J; Department of Hepatobiliary Surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan 250117, China.
Jazyk: angličtina
Zdroj: Oxidative medicine and cellular longevity [Oxid Med Cell Longev] 2020 Mar 24; Vol. 2020, pp. 7079308. Date of Electronic Publication: 2020 Mar 24 (Print Publication: 2020).
DOI: 10.1155/2020/7079308
Abstrakt: Hepatocellular carcinoma (HCC) is regarded as a leading cause of cancer-related deaths, and its progression is associated with hypoxia and the induction of hypoxia-inducible factor (HIF). Meloxicam, a selective cyclooxygenase-2 (COX-2) inhibitor, induces cell death in various malignancies. However, the underlying mechanism remains to be elucidated in HCC, especially under hypoxic conditions. The alteration of COX-2 and HIF-1 α oncogenicity was evaluated in HCC specimens by tissue microarray. Cell viability, angiogenesis assays, and xenografted nude mice were used to evaluate the effects of meloxicam, along with flow cytometry to detect the cell cycle, apoptosis, and mitochondrial membrane potential ( ΔΨm ) of HCC. qRT-PCR, Western blotting, immunofluorescence, immunohistochemistry, luciferase assay, and RNAi were carried out to determine the HIF-1 α signaling affected by meloxicam. In this study, we showed that meloxicam exerts antiproliferative and antiangiogenesis efficacy in vitro and in vivo and causes disruption of mitochondrial membrane potential ( ΔΨm ), thus leading to caspase-dependent apoptosis under hypoxic environments. Exposure to meloxicam significantly reduced HIF-1 α transcriptional activation and expression through sequestering it in the cytoplasm and accelerating degradation via increasing the von Hippel-Lindau tumor suppressor protein (pVHL) in HCC. These data demonstrated that inhibition of HIF-1 α by meloxicam could suppress angiogenesis and enhance apoptosis of HCC cells. This discovery highlights that COX-2 specific inhibitors may be a promising therapy in the treatment of HCC.
Competing Interests: The authors declare no potential conflicts of interest.
(Copyright © 2020 Yinghong Zhou et al.)
Databáze: MEDLINE
Externí odkaz: