COX-2 overexpression increases malignant potential of human glioma cells through Id1

Abstract

Increased COX-2 expression directly correlates with glioma grade and is associated with shorter survival in glioblastoma (GBM) patients. COX-2 is also regulated by epidermal growth factor receptor signaling which is important in the pathogenesis of GBMs. However, COX-2 expression has not been previously shown to directly alter malignancy of GBMs. Id1 is a member of the helix-loop-helix (HLH) family of transcriptional repressors that act as dominant-negative inhibitors of basic-HLH factors. This factor has been shown to be regulated by COX-2 in breast carcinoma cells and recent studies suggest that Id1 may also be involved in the genesis/progression of gliomas. We now show that COX-2 increases the aggressiveness of GBM cells. GBM cells with COX-2 overexpression show increased growth of colonies in soft agar. Tumorigenesis in vivo is also increased in both subcutaneous flank and orthotopic intracranial tumor models. COX-2 overexpression induces Id1 expression in two GBM cell lines suggesting a role for Id1 in glioma transformation/tumorigenesis. Furthermore, we find direct evidence of a role for Id1 with significant suppression of in vitro transformation and in vivo tumorigenesis in COX-2-overexpressing GBM cells where Id1 has been knocked down. In fact, Id1 is even more efficient at enhancing transformation/tumorigenesis of GBM cells than COX-2. Finally, GBM cells with COX-2 or Id1 overexpression show greater migration/invasive potential and tumors that arise from these cells also display increased microvessel density, results in line with the increased malignant potential seen in these cells. Thus, COX-2 enhances the malignancy of GBM cells through induction of Id1.

Radiation-induced PGE2sustains human glioma cell growth and survival through EGF signaling

“…Recently, COX2 and PGE 2 have been implicated in cancer progression but mixed results were obtained with COX2 inhibitors and radio-sensitization [34, 35]. Our results provide a molecular mechanism, by which PGE 2 can sustain tumor growth and proliferation after tumor irradiation and support new alternative targets, such as EP2, to potentiate the effect of radiotherapy.…”

Exogenous hydrogen sulfide exerts proliferation/anti-apoptosis/angiogenesis/migration effects via amplifying the activation of NF-κB pathway in PLC/PRF/5 hepatoma cells

“…In our observational study, treatment with 500 µmol/l NaHS for 24 h obviously promoted protein COX-2 secretion in PLC/PRF/5 hepatoma cells. Importantly, accumulating evidence has demonstrated that cyclooxygenase (COx)-2 is overexpressed in several types of cancers cells (73)(74)(75) including hepatocellular carcinoma (HCC) (76). COX-2 expression in cells and animal models is closely associated with tumor cell growth and is a crucial molecule in the development of malignant tumors, including promotion of angiogenesis (77), anti-apoptotic effects (78), invasiveness of tumor cells (74), and tumor cell proliferation (79), demonstrating that COX-2 pathway is implicated in NaHS-induced PLC/PRF/5 hepatoma cell proliferation, anti-apoptosis, angiogenesis and migration.…”

3d metal complexes with meloxicam as therapeutic agents in the fight against human glioblastoma multiforme and cervical carcinoma

“…[46] Furthermore, increased COX-2 expression has been shown to directly correlate with glioma grade and to be associated with shorter survival in glioblastoma multiforme patients. [47] In addition, there are data that COX-2 regulates the proliferation of glioma stem like cells. [48] (2) Promising antitumour activity of meloxicam has been demonstrated in prostate [49] and colorectal [50] cancer cell lines, hepatocellular carcinoma [51] and osteosarcoma.…”