Possible Therapeutic Strategy Involving the Purine Synthesis Pathway Regulated by ITK in Tongue Squamous Cell Carcinoma

The epidermal growth factor receptor is the only available tyrosine kinase molecular target for treating oral cancer. To improve the prognosis of tongue squamous cell carcinoma (TSCC) patients, a novel molecular target for tyrosine kinases is thus needed. We examined the expression of interleukin-2–...

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Bibliographic Details
Published in:Cancers 2021-07, Vol.13 (13), p.3333
Main Authors: Onidani, Kaoru, Miura, Nami, Sugiura, Yuki, Abe, Yuichi, Watabe, Yukio, Kakuya, Takanori, Mori, Taisuke, Yoshimoto, Seiichi, Adachi, Jun, Kiyoi, Takao, Kabe, Yasuaki, Suematsu, Makoto, Tomonaga, Takeshi, Shibahara, Takahiko, Honda, Kazufumi
Format: Article
Language:English
Subjects:
Adenosine
Animal models
Biosynthesis
Cancer
Cell culture
Cell growth
Cell proliferation
Epidermal growth factor
Gene expression
Immunohistochemistry
Inoculation
Interleukin 2
Itk protein
Kinases
Lymphocytes
Lymphocytes T
Mass spectrometry
Medical prognosis
Melanoma
Metabolomics
Monoclonal antibodies
Patients
Phase transitions
Phenotypes
Phosphorylation
Prognosis
Protein expression
Protein-tyrosine kinase
Proteins
Proteomics
Purines
Scientific imaging
Squamous cell carcinoma
Surfactants
Tongue
Transfection
Tumor cell lines
Tumors
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Summary:The epidermal growth factor receptor is the only available tyrosine kinase molecular target for treating oral cancer. To improve the prognosis of tongue squamous cell carcinoma (TSCC) patients, a novel molecular target for tyrosine kinases is thus needed. We examined the expression of interleukin-2–inducible T-cell kinase (ITK) using immunohistochemistry, and the biological function of ITK was investigated using biochemical, phosphoproteomic, and metabolomic analyses. We found that ITK is overexpressed in TSCC patients with poor outcomes. The proliferation of oral cancer cell lines expressing ITK via transfection exhibited significant increases in three-dimensional culture assays and murine inoculation models with athymic male nude mice as compared with mock control cells. Suppressing the kinase activity using chemical inhibitors significantly reduced the increase in cell growth induced by ITK expression. Phosphoproteomic analyses revealed that ITK expression triggered phosphorylation of a novel tyrosine residue in trifunctional purine biosynthetic protein adenosine-3, an enzyme in the purine biosynthesis pathway. A significant increase in de novo biosynthesis of purines was observed in cells expressing ITK, which was abolished by the ITK inhibitor. ITK thus represents a potentially useful target for treating TSCC through modulation of purine biosynthesis.
ISSN:2072-6694
2072-6694
DOI:10.3390/cancers13133333