Dataset Information

Mevalonate pathway activity is a key determinant of radiation sensitivity in head and neck cancer

ABSTRACT: Radioresistance is a major hurdle in the treatment of head and neck squamous cell carcinoma (HNSCC). Here we report a novel role for statin-based treatment of HNSCCs as an actionable and safe adjuvant to radiotherapy. Proteomic profiling and comparison of radiosensitive and radioresistant HNSCCs revealed differential regulation of the mevalonate biosynthetic pathway. Consistent with this finding, inhibition of the mevalonate pathway by pitavastatin (and other related statins) sensitized SQ20B cells to ionizing radiation (IR) and reduced their clonogenic potential. In an effort to uncover the mechanism behind this statin-mediated sensitization, we analyzed prenylation of several important cellular targets upon combined IR-statin treatment. Overall, this study reinforces the view that the mevalonate pathway is a promsing novel therapeutic target in radioresistant HSNCCs.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Permanent Cell Line Cell

DISEASE(S): Head And Neck Cancer

SUBMITTER: Donald Wolfgeher

LAB HEAD: Dr. Stephen J Kron

PROVIDER: PXD007188 | Pride | 2019-06-25

REPOSITORIES: Pride

ACCESS DATA

Publications

Mevalonate pathway activity as a determinant of radiation sensitivity in head and neck cancer.

Ricco Natalia N Flor Amy A Wolfgeher Don D Efimova Elena V EV Ramamurthy Aishwarya A Appelbe Oliver K OK Brinkman Jacqueline J Truman Andrew W AW Spiotto Michael T MT Kron Stephen J SJ

Molecular oncology 20190726 9

Radioresistance is a major hurdle in the treatment of head and neck squamous cell carcinoma (HNSCC). Here, we report that concomitant treatment of HNSCCs with radiotherapy and mevalonate pathway inhibitors (statins) may overcome resistance. Proteomic profiling and comparison of radioresistant to radiosensitive HNSCCs revealed differential regulation of the mevalonate biosynthetic pathway. Consistent with this finding, inhibition of the mevalonate pathway by pitavastatin sensitized radioresistant ...[more]

PMID: 31225926

Similar Datasets

Project description: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 comparison of protein expression in MIA PaCa-2 and MIA PaCa-2-R cells revealed that several growth factor- and cytokine-mediated pathways, including the OSM/STAT3, PI3K/AKT and MAPK/ERK pathways, were activated in the radioresistant cells, leading to enhanced cell migration, invasion and epithelial-mesenchymal transition (EMT), and inhibition of apoptosis. We focused functional analysis on one of the most upregulated proteins in the radioresistant cells, CD73, which is a cell surface protein that is overexpressed in a variety types of cancer. Ectopic overexpression of CD73 in the parent cells resulted in radioresistance and conferred resistance to IR-induced apoptosis. Knockdown of CD73 resensitized 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 suggest that CD73 confers acquired radioresistance in pancreatic cancer cells at least in part through inactivating proapoptotic protein BAD via phosphorylation of BAD at Ser-136. Furthermore, we found that knockdown of CD73 in the radioresistant cells alone reverted the gene expression and phenotype of the radioresistant cells from those of mesenchymal-like cells to the ones of epithelial cells, demonstrating that CD73 upregulation is required for maintaining EMT in the radioresistant cells. Our results support the notion that the enhanced growth factor/cytokine signaling that promotes epithelial-mesenchymal plasticity, and acquisition of cancer stem-like cell properties contributes to acquired radioresistance in the residual surviving cells after fractionated irradiation, and that CD73 is a novel downstream factor of those enhanced signaling and acts to confers acquired radioresistance and maintains EMT in the radioresistant pancreatic cancer cells.

Dataset Information

Mevalonate pathway activity is a key determinant of radiation sensitivity in head and neck cancer

Publications

Mevalonate pathway activity as a determinant of radiation sensitivity in head and neck cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure