Abstract
The molecular mechanisms underlying exceptional radioresistance in pancreatic cancer remain elusive. In the present study, we established a stable radioresistant pancreatic cancer cell line MIA PaCa-2-R by exposing the parental MIA PaCa-2 cells to fractionated ionizing radiation (IR). Systematic proteomics and bioinformatics analysis of protein expression in MIA PaCa-2 and MIA PaCa-2-R cells revealed that several growth factor-/cytokine-mediated pathways, including the OSM/STAT3, PI3K/AKT, and MAPK/ERK pathways, were activated in the radioresistant cells, leading to inhibition of apoptosis and increased epithelial-mesenchymal plasticity. In addition, the radioresistant cells exhibited enhanced capabilities of DNA repair and antioxidant defense compared with the parental cells. We focused functional analysis on one of the most up-regulated proteins in the radioresistant cells, ecto-5'-nucleotidase (CD73), which is a cell surface protein that is overexpressed in different types of cancer. Ectopic overexpression of CD73 in the parental cells resulted in radioresistance and conferred resistance to IR-induced apoptosis. Knockdown of CD73 re-sensitized the radioresistant cells to IR and IR-induced apoptosis. The effect of CD73 on radioresistance and apoptosis is independent of the enzymatic activity of CD73. Further studies demonstrate that CD73 up-regulation promotes Ser-136 phosphorylation of the proapoptotic protein BAD and is required for maintaining the radioresistant cells in a mesenchymal state. Our findings suggest that expression alterations in the IR-selected pancreatic cancer cells result in hyperactivation of the growth factor/cytokine signaling that promotes epithelial-mesenchymal plasticity and enhancement of DNA repair. Our results also suggest that CD73, potentially a novel downstream factor of the enhanced growth factor/cytokine signaling, confers acquired radioresistance by inactivating proapoptotic protein BAD via phosphorylation of BAD at Ser-136 and by maintaining the radioresistant pancreatic cancer cells in a mesenchymal state.
Highlights
Upregulation of CD73 Confers Acquired Radioresistance and is Required for Maintaining Irradiation-selected Pancreatic Cancer Cells in a Mesenchymal State*□S
Our results suggest that CD73, potentially a novel downstream factor of the enhanced growth factor/cytokine signaling, confers acquired radioresistance by inactivating proapoptotic protein BAD via phosphorylation of BAD at Ser-136 and by maintaining the radioresistant pancreatic cancer cells in a mesenchymal state
The results demonstrated that several growth factor- or cytokinemediated pathways, including the oncostatin M (OSM)/signal transducer and activator of transcription 3 (STAT3), phosphatidylinositide 3-kinase (PI3K)/␣-serine/threonine-protein kinase (AKT), and mitogen-activated protein kinase (MAPK)/ extracellular signal-regulated kinase (ERK) pathways, were activated in the radioresistant cells, leading to inhibition of apoptosis and a higher degree of epithelial-mesenchymal plasticity
Summary
A LC-MS/MS-based quantitative proteomic analysis reveals that expression alterations in the irradiation-selected pancreatic cancer cells result in hyperactivation of the growth factor/cytokine signaling that promotes epithelialmesenchymal plasticity and enhancement of DNA repair. Our findings suggest that expression alterations in the IR-selected pancreatic cancer cells result in hyperactivation of the growth factor/cytokine signaling that promotes epithelial-mesenchymal plasticity and enhancement of DNA repair. Our results suggest that CD73, potentially a novel downstream factor of the enhanced growth factor/cytokine signaling, confers acquired radioresistance by inactivating proapoptotic protein BAD via phosphorylation of BAD at Ser-136 and by maintaining the radioresistant pancreatic cancer cells in a mesenchymal state. The results demonstrated that several growth factor- or cytokinemediated pathways, including the oncostatin M (OSM)/signal transducer and activator of transcription 3 (STAT3), phosphatidylinositide 3-kinase (PI3K)/␣-serine/threonine-protein kinase (AKT), and mitogen-activated protein kinase (MAPK)/ extracellular signal-regulated kinase (ERK) pathways, were activated in the radioresistant cells, leading to inhibition of apoptosis and a higher degree of epithelial-mesenchymal plasticity. Functional analysis of one of the most up-regulated proteins in the radioresistant cells, CD73, revealed that CD73 up-regulation confers acquired radioresistance in the radioresistant cells and the action is, at least in part, through inactivating the proapoptotic protein BAD by causing BAD phosphorylation at Ser-136 and through maintaining the IR-selected cells in a mesenchymal state
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