Elevated N-myristoyltransferase activity and expression in oral squamous cell carcinoma

Shrivastav, Anuraag; Sharma, Anil; Bajaj, Gagan; Charavaryamath, Chandrashekhar; Ezzat, Wendelin; Spafford, Peter; Gore-Hickman, Rick; Copete, Maria; Sharma, Rajendra K.

doi:10.3892/or.18.1.93

Cited by 11 publications

(11 citation statements)

References 27 publications

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“…Further research will be necessary to determine the specific targets of tris DBA at cilia as well as the signaling mechanisms that regulate cilia-dependent directed migration in pancreatic cancer cells. Several studies suggest that NMT1 activity is important for the progression of different malignancies including breast cancer [31], oral squamous cell carcinoma [32], colon carcinoma [33] and gallblader cancer [34]. Our findings suggest that NMT1 is a novel therapeutic target in pancreatic cancer and warrants further investigation of tris DBA as a potential novel treatment for pancreatic carcinoma.…”

Section: Discussionmentioning

confidence: 57%

Tris DBA palladium is highly effective against growth and metastasis of pancreatic cancer in an orthotopic model

et al. 2016

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Pancreatic carcinoma ranks among the most lethal of human cancers. Besides late detection, other factors contribute to its lethality, including a high degree of chemoresistance, invasion, and distant metastases. Currently, the mainstay of therapy involves resection of local disease in a minority of patients (Whipple procedure) and systemic gemcitabine. While systemic chemotherapy has some benefit, even with optimal treatment, the five year survival after diagnosis is dismal. Thus, treatment of pancreatic carcinoma remains a tremendous unmet need.The organometallic compound tris DBA palladium is a potent inhibitor of N-myristoyltransferase 1 (NMT1), an enzyme that catalyzes the transfer of myristate to protein substrates. This compound is highly effective in vivo against murine models of melanoma with both mutant and wild type b-RAF genotypes. Based upon the signaling similarities between melanoma and pancreatic carcinoma, we evaluated the efficacy of tris DBA palladium in vitro and in vivo against pancreatic carcinoma. We found that tris DBA palladium decreased proliferation and colony formation of pancreatic cancer cells in vitro. In an orthotopic mouse model, tris DBA palladium was highly active in inhibiting growth, ascites production, and distant metastases in vivo. Furthermore, tris DBA palladium impaired chemotaxis and inhibited cilia formation in Pan02 cells in a NMT1-dependent manner. We propose that NMT1 is a novel regulator of cilia formation and tris DBA palladium a novel inhibitor of cilia formation and metastasis in pancreatic cancer. Thus, further evaluation of tris DBA palladium for the treatment of pancreatic cancer is warranted.

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Section: Discussionmentioning

confidence: 57%

Tris DBA palladium is highly effective against growth and metastasis of pancreatic cancer in an orthotopic model

et al. 2016

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“…354 These results suggest that NMT might be a potential biomarker or target for colon cancer. 355 Similarly, several studies have demonstrated that NMT expression is elevated in oral squamous cell carcinoma, 356 gallbladder carcinoma, 357 and brain tumors. 235 Moreover, a cyclohexyl-octahydropyrrolo[1,2-a]pyrazine based NMT1 inhibitor, COPP-24 (Figure 17), has been shown to inhibit the proliferation of some tumor cancer cell lines.…”

Section: N-terminal Glycine Myristoylationmentioning

confidence: 97%

Protein Lipidation: Occurrence, Mechanisms, Biological Functions, and Enabling Technologies

et al. 2018

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Protein lipidation, including cysteine prenylation, N-terminal glycine myristoylation, cysteine palmitoylation, and serine and lysine fatty acylation, occurs in many proteins in eukaryotic cells and regulates numerous biological pathways, such as membrane trafficking, protein secretion, signal transduction, and apoptosis. We provide a comprehensive review of protein lipidation, including descriptions of proteins known to be modified and the functions of the modifications, the enzymes that control them, and the tools and technologies developed to study them. We also highlight key questions about protein lipidation that remain to be answered, the challenges associated with answering such questions, and possible solutions to overcome these challenges.

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“…Over-expression also occurs relatively early in carcinogenesis, in colonic polyps that are not yet malignant [119]. There is also evidence for the overexpression of NMT in gallbladder and oral squamous cell carcinomas [121,122] and brain tumours [123]. Clegg and co-workers have looked at NMT in mammary epithelial cells and found that proliferative capacity correlated with NMT activity [124].…”

Section: Nmt In Cancermentioning

confidence: 99%

Protein myristoylation in health and disease

et al. 2009

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N-myristoylation is the attachment of a 14-carbon fatty acid, myristate, onto the N-terminal glycine residue of target proteins, catalysed by N-myristoyltransferase (NMT), a ubiquitous and essential enzyme in eukaryotes. Many of the target proteins of NMT are crucial components of signalling pathways, and myristoylation typically promotes membrane binding that is essential for proper protein localisation or biological function. NMT is a validated therapeutic target in opportunistic infections of humans by fungi or parasitic protozoa. Additionally, NMT is implicated in carcinogenesis, particularly colon cancer, where there is evidence for its upregulation in the early stages of tumour formation. However, the study of myristoylation in all organisms has until recently been hindered by a lack of techniques for detection and identification of myristoylated proteins. Here we introduce the chemistry and biology of N-myristoylation and NMT, and discuss new developments in chemical proteomic technologies that are meeting the challenge of studying this important co-translational modification in living systems.Keywords Post-translational modification . Drug design . Myristoylation . Lipidation . Chemical proteomics Post-translational modification and myristoylationThe proteome is a larger and more dynamic entity than the genome, a result of both increased sequence diversity at the mRNA level due to alternative splicing of genes, and increased chemical and functional complexity at the protein level due to post-translational modification (PTM). This explains to some extent why larger genomes do not necessarily translate into more complex organisms. Posttranslational modification allows the incorporation of chemistries and new molecular functions that cannot be directly encoded by the gene sequence. Myristoylation is the attachment of a 14-carbon saturated fatty acid, myristate, to the N-terminal glycine of a subset of eukaryotic proteins [8,16,17]. Although often referred to as a PTM, it usually occurs co-translationally [18], when fewer than 100 residues have been polymerised by the

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Elevated N-myristoyltransferase activity and expression in oral squamous cell carcinoma

Cited by 11 publications

References 27 publications

Tris DBA palladium is highly effective against growth and metastasis of pancreatic cancer in an orthotopic model

Tris DBA palladium is highly effective against growth and metastasis of pancreatic cancer in an orthotopic model

Protein Lipidation: Occurrence, Mechanisms, Biological Functions, and Enabling Technologies

Protein myristoylation in health and disease

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