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

Natalia Ricco,Oliver K Appelbe,Jacqueline Brinkman,Aishwarya Ramamurthy,Andrew W Truman,Don Wolfgeher,Amy Flor,Elena V Efimova,Stephen J Kron,Michael T Spiotto

doi:10.1002/1878-0261.12535

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.

Highlights

Radiotherapy remains one of the most widely used treatments for cancer as nearly half of patients receive it alone or in combination with other types of therapies (Delaney et al, 2005)
Radiosensitive (SCC61) and radioresistant (JSQ3 and SQ20B) head and neck squamous cell carcinoma (HNSCC) human cancer cell lines were grown under standard culture conditions, and after protein isolation and digestion in biological triplicates, peptides were analyzed by local control (LC)-liquid chromatography tandem mass spectrometry (MS)/MS mass spectrometry
In order to analyze the proteomic signature of radioresistant cells, label-free quantitation (LFQ) was conducted using the mass spectrometry intensities for all the protein hits identified in a minimum of 2 of 3 biological replicates

Summary

Introduction

Radiotherapy remains one of the most widely used treatments for cancer as nearly half of patients receive it alone or in combination with other types of therapies (Delaney et al, 2005). Head and neck squamous cell carcinomas include a broad category of neoplasms that primarily develop in the oral cavity, pharynx, and larynx and are the sixth leading cause of cancer worldwide with approximately. Abbreviations a.u., arbitrary units; DSB, double-strand break; FDPS, farnesyl diphosphate synthase; FPP, farnesyl pyrophosphate; GGPP, geranylgeranyl pyrophosphate; GGPS, geranylgeranyl diphosphate synthase; HMGCR, 3-hydroxy-methylglutaryl HMG-CoA reductase; HMGCS1, 3-hydroxy3-methylglutaryl-CoA synthase 1; HNSCC, head and neck squamous cell cancer; IPP, isopentenyl diphosphate; IR, ionizing radiation; LC-MS/ MS, liquid chromatography tandem mass spectrometry; LDL, low-density lipoprotein; LDLR, low-density lipoprotein receptor; LFQ, label-free quantification; LRP1, prolow-density lipoprotein receptor-related protein 1; M5P, mevalonate-5-phosphate; M5PP, mevalonate-5-diphosphate; MFI, mean fluorescence intensity; MVD, mevalonate decarboxylase; MVK, mevalonate kinase; NSDHL, NAD(P) dependent steroid dehydrogenase-like; PIT, pitavastatin; PMVK, phosphomevalonate kinase; SD, standard deviation; STR, short tandem repeats.

Methods

Results

Conclusion