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Meloxicam, a Selective COX-2 Inhibitor, Mediates Hypoxia-Inducible Factor- (HIF-) 1α Signaling in Hepatocellular Carcinoma
- Source :
- Oxidative Medicine and Cellular Longevity, Oxidative Medicine and Cellular Longevity, Vol 2020 (2020)
- Publication Year :
- 2020
- Publisher :
- Hindawi, 2020.
-
Abstract
- 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-1α 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-1α 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-1α 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-1α 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.
- Subjects :
- 0301 basic medicine
Aging
Programmed cell death
Carcinoma, Hepatocellular
Article Subject
Angiogenesis
Mice, Nude
Meloxicam
Transfection
Biochemistry
03 medical and health sciences
Mice
0302 clinical medicine
medicine
Animals
Humans
Viability assay
QH573-671
Cyclooxygenase 2 Inhibitors
Chemistry
Liver Neoplasms
Cell Biology
General Medicine
Cell cycle
Middle Aged
Hypoxia-Inducible Factor 1, alpha Subunit
030104 developmental biology
Hypoxia-inducible factors
Apoptosis
030220 oncology & carcinogenesis
Cancer research
COX-2 inhibitor
Cytology
medicine.drug
Research Article
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 19420900
- Database :
- OpenAIRE
- Journal :
- Oxidative Medicine and Cellular Longevity
- Accession number :
- edsair.doi.dedup.....f3198bc8fe3acdabc402d48d26cc869a
- Full Text :
- https://doi.org/10.1155/2020/7079308