Protein Farnesylation on Nasopharyngeal Carcinoma, Molecular Background and Its Potential as a Therapeutic Target

Abstract

Nasopharyngeal carcinoma (NPC) is one of the Epstein–Barr virus (EBV)-associated malignancies. NPC is highly metastatic compared to other head and neck carcinomas, and evidence has shown that the metastatic features of NPC are involved in EBV infection. The prognosis of advanced cases, especially those with distant metastasis, is still poor despite advancements in molecular research and its application to clinical settings. Thus, further advancement in basic and clinical research that may lead to novel therapeutic modalities is needed. Farnesylation is a lipid modification in the C-terminus of proteins. It enables proteins to attach to the lipid bilayer structure of cellular membranes. Farnesylation was initially identified as a key process of membrane association and activation of the RAS oncoprotein. Farnesylation is thus expected to be an ideal therapeutic target in anti-RAS therapy. Additionally, more and more molecular evidence has been reported, showing that proteins other than RAS are also farnesylated and have significant roles in cancer progression. However, although several clinical trials have been conducted in cancers with high rates of ras gene mutation, such as pancreatic carcinomas, the results were less favorable than anticipated. In contrast, favorable outcomes were reported in the results of a phase II trial on head and neck carcinoma. In this review, we provide an overview of the molecular pathogenesis of NPC in terms of the process of farnesylation and discuss the potential of anti-farnesylation therapy in the treatment of NPC.

Statins as anti‐tumor agents: A paradigm for repurposed drugs

“…Statin treatment inhibits the production of these signaling components thereby curbing tumor progression 140,241,242 . Farnesylation and Geranylgeranylation are the two isoprenyl modifications that are crucial for signaling, especially in tumor progression 243,244 . Reports of active role of Rho family of GTPases in tumorigenesis 245 have initiated the search for their potent inhibitors as cancer therapeutics 246,247 .…”

“… 140 , 241 , 242 Farnesylation and Geranylgeranylation are the two isoprenyl modifications that are crucial for signaling, especially in tumor progression. 243 , 244 Reports of active role of Rho family of GTPases in tumorigenesis 245 have initiated the search for their potent inhibitors as cancer therapeutics. 246 , 247 It is well‐established that statin‐mediated inhibition of isoprenylation in small GTPases has a direct impact on oncogenic signaling, thereby preventing tumor initiation and making statins one of the candidates.…”

Cholesterol: An important actor on the cancer immune scene

“…Elucidating the cholesterol synthesis pathway is important because mediators and intermediate enzymes affect the cancer process. For example, C-terminal farnesylation of proteins leads to the formation of a hydrophobic tail, thus enabling lipid-protein and protein-protein interaction (23)(24)(25). Indeed, farnesylation is a necessary step for RAS oncoprotein activation and cell membrane binding.…”

How Should We Deal with Neoplastic Disease and Serious Infections Caused by Epstein–Barr Virus?

“…Since then, more and more evidence has accumulated that proteins other than RAS are also farnesylated and play an important role in carcinogenesis. Kobayashi E et al reviews the molecular pathogenesis of protein farnesylation in nasopharyngeal carcinoma and discusses the potential of farnesylation as a therapeutic target [9].…”