Abstract
Hypoxia decreases cytotoxic responses to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) protein. Cellular prion protein (PrPc) is regulated by HIF-1α in neurons. We hypothesized that PrPc is involved in hypoxia-mediated resistance to TRAIL-induced apoptosis. We found that hypoxia induced PrPc protein and inhibited TRAIL-induced apoptosis. Thus silencing of PrPc increased TRAIL-induced apoptosis under hypoxia. Overexpression of PrPc protein using an adenoviral vector inhibited TRAIL-induced apoptosis. In xenograft model in vivo, shPrPc transfected cells were more sensitive to TRAIL-induced apoptosis than in shMock transfected cells. Molecular chemo-therapy approaches based on the regulation of PrPc expression need to address anti-tumor function of TRAIL under hypoxia. Molecular chemo-therapy approaches based on the regulation of PrPc expression need to address anti-tumor function of TRAIL under hypoxia.
Highlights
Tumor necrosis factor (TNF)-related apoptosisinducing ligand (TRAIL), known as the Apo2 ligand, is a membrane-bound cytokine
We investigated whether silencing of PrPc protein under hypoxic condition would blocks inhibition of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced tumor cell apoptosis and PrPc overexpression is associated with resistance to TRAIL-induced apoptosis under hypoxic or normal oxygen conditions in colon cancer cells
These results indicate that over expression of PrPC was related with HIF-1α, and as such, are possible mechanisms involved in the hypoxic conditions of HCT116 cells
Summary
Tumor necrosis factor (TNF)-related apoptosisinducing ligand (TRAIL), known as the Apo ligand, is a membrane-bound cytokine. Biologically and therapeutically important hypoxia occurs in many solid tumor masses [9], as the center of rapidly growing solid tumors is exposed to hypoxic conditions [10] This cell response to hypoxia is an adverse prognostic indicator in cancer, as it is associated with tumor progression and resistance to therapy [11,12,13]. Recent findings show that hypoxia increases the anti-apoptotic potential of tumor cells by regulating the molecules involved in apoptosis signaling pathways [14] These effects of hypoxia render tumor cells resistant to various cancer therapies including TRAIL treatment and facilitate survival of tumor cells [12, 15]
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