Possible therapeutic strategy involving the purine synthesis pathway regulated by itk in tongue squamous cell carcinoma

Kaoru Onidani, Nami Miura, Yuki Sugiura, Yuichi Abe, Yukio Watabe, Takanori Kakuya, Taisuke Mori, Seiichi Yoshimoto, Jun Adachi, Takao Kiyoi, Yasuaki Kabe, Makoto Suematsu, Takeshi Tomonaga, Takahiko Shibahara, Kazufumi Honda

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Article number3333
JournalCancers
Volume13
Issue number13
DOIs
Publication statusPublished - 2021 Jul 1

Keywords

  • IL2-inducible T-cell kinase (ITK)
  • Tongue squamous cell carcinoma
  • Trifunctional purine biosynthetic protein adenosine-3 (GART)

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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