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.
Highlights
Hepatocellular carcinoma (HCC) ranks sixth among the most common carcinoma and is the fourth leading cause of cancer-related death worldwide [1]
When the oxygen concentration declines, expression of hypoxia-inducible factor (HIF)-1α exponentially increases which allows it to dimerize with the Hypoxia-inducible factor- (HIF-)1β subunit to form hypoxia response elements (HREs) regulating targeted genes involved in the process of tumoral angiogenesis, proliferation, metastasis, and apoptosis of cancer cells [8, 9]
There was no significant correlation between COX-2 expression and clinicopathological variables including patient age, sex, histology grade, and lymph node metastasis (Table 1)
Summary
Hepatocellular carcinoma (HCC) ranks sixth among the most common carcinoma and is the fourth leading cause of cancer-related death worldwide [1]. Orthotopic liver transplantation, and radiofrequency ablation are very effective therapeutic strategies in the early stage of HCC whereas most HCC patients are in an advanced stage of disease while diagnosed. There is an urgent need to better understand these mechanisms and develop new therapeutics for HCC treatment. In HCC, the degree of tumor hypoxia appears to be inversely related to the patient’s prognosis. When the oxygen concentration declines, expression of HIF-1α exponentially increases which allows it to dimerize with the HIF-1β subunit to form hypoxia response elements (HREs) regulating targeted genes involved in the process of tumoral angiogenesis, proliferation, metastasis, and apoptosis of cancer cells [8, 9]
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