Deregulated expression and activity of Farnesyl Diphosphate Synthase (FDPS) in Glioblastoma

Mario Abate,Chiara Laezza,Giovanni Torelli,Maria Notarnicola,Vincenzo Seneca,Francesco Montella,Maurizio Bifulco,Simona Pisanti,Giuseppe Catapano,Roberta Ranieri,Patrizia Gazzerro,Elena Ciaglia

doi:10.1038/s41598-017-14495-6

Abstract

Glioblastoma (GBM), the most aggressive brain cancer, is highly dependent on the mevalonate (MVA) pathway for the synthesis of lipid moieties critical for cell proliferation but the function and regulation of key intermediate enzymes like farnesyl-diphosphate synthase (FDPS), up to now, remained unknown. A deregulated expression and activity of FDPS was the central research idea of the present study. FDPS mRNA, protein and enzyme activity were analyzed in a cohort of stage III-IV glioma patients (N = 49) and primary derived cells. FDPS silencing helped to clarify its function in the maintenance of malignant phenotype. Interestingly, compared to tumor-free peripheral (TFB) brain and normal human astrocytes (NHA), FDPS protein expression and enzyme activity were detected at high degree in tumor mass where a correlation with canonical oncogenic signaling pathways such as STAT3, ERK and AKT was also documented. Further, FDPS knockdown in U87 and GBM primary cells but not in NHA, enhanced apoptosis. With the effort to develop a more refined map of the connectivity between signal transduction pathways and metabolic networks in cancer FDPS as a new candidate metabolic oncogene in glioblastoma, might suggest to further target MVA pathway as valid therapeutic tool.

Highlights

The control of cellular metabolism is essential for a normal cell behavior, and the role that aberrant cellular metabolism has in cancer is becoming increasingly evident
Given the putative oncogenic role of an aberrant mevalonate pathway in glioblastoma, we looked for potential expression changes of the Farnesyl Diphosphate Synthase (FDPS) key intermediate enzyme in patients
Eventhough without any apparent association with tumor type and grade (Fig. 1E), FDPS was found upregulated in terms both of mRNA and protein levels in glioma patients samples compared with normal human astrocytes (NHA) and peripheral tumor free brains (Fig. 1A,B)

Summary

OPEN Deregulated expression and activity of Farnesyl Diphosphate

Mario Abate[1], Chiara Laezza[2,3], Simona Pisanti[1], Giovanni Torelli[4], Vincenzo Seneca[5], Giuseppe Catapano[5], Francesco Montella[1], Roberta Ranieri[1], Maria Notarnicola[6], Patrizia Gazzerro 7, Maurizio Bifulco1,3 & Elena Ciaglia 1. Glioblastoma (GBM), the most aggressive brain cancer, is highly dependent on the mevalonate (MVA) pathway for the synthesis of lipid moieties critical for cell proliferation but the function and regulation of key intermediate enzymes like farnesyl-diphosphate synthase (FDPS), up to now, remained unknown. As recently found in U343MG glioma cells, the notable tumor suppressor p53 was able to induce the expression of a group of enzymes of the MVA pathway including HMGCoA reductase, MVA kinase, FDPS and farnesyl diphosphate farnesyl transferase 13. In human U87MG glioma cell line, FDPS played an important role in attenuating paclitaxel-induced cell death by affecting p53 and c-Jun N-terminal kinase (JNK)[16]. Overall, these findings prompted us to better underpin the contribution of FDPS to malignant gliomas

Material and Methods

Results and Discussion

Author Contributions

Additional Information