Mevalonate pathway activity as a determinant of radiation sensitivity in head and neck cancer. Issue 9 (26th July 2019)

• Record Type: Journal Article
• Authors: Ricco, Natalia; Flor, Amy; Wolfgeher, Don; Efimova, Elena V.; Ramamurthy, Aishwarya; Appelbe, Oliver K.; Brinkman, Jacqueline; Truman, Andrew W.; Spiotto, Michael T.; Kron, Stephen J.
• Is Part Of: Molecular oncology. Volume 13:Issue 9(2019)
• Page Start: 1927
• Page End: 1943
• Publication Date: 2019-07-26
• Subjects: DNA damage response -- HNSCC -- mevalonate pathway -- radiation sensitivity -- senescence -- statin; Cancer -- Molecular aspects -- Periodicals; 616.994005
• DOI: 10.1002/1878-0261.12535
• Languages: English
• ISSNs: 1574-7891

Abstract

Abstract : 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 SQ20B cells to ionizing radiation and reduced their clonogenic potential. Overall, this study reinforces the view that the mevalonate pathway is a promising therapeutic target in radioresistant HNSCCs. Abstract : Radioresistant HNSCC cell lines present dysregulation of proteins in the mevalonate pathway, as well as elevated cholesterol content, increased LDL receptor abundance, and high levels of LDL uptake. Radioresistant cells displayed loss of cell viability, decreased clonogenic potential, an increase in DNA damage, and induction of cell senescence when treated with the mevalonate pathway inhibitor pitavastatin along with radiation.