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Modeling Spontaneous Metastatic Renal Cell Carcinoma mRCC in Mice Following Nephrectomy
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GAMT facilitates tumor progression via inhibiting p53 in clear cell renal cell carcinoma

Bin Zheng1,2, Kan Liu1,2, Ji Feng1,2

  • 1Medical School of Chinese PLA, Beijing, 100853, China.

Biology Direct
|April 2, 2025
PubMed
Abstract

Insights

The enzyme GAMT promotes clear cell renal cell carcinoma (ccRCC) progression by inhibiting p53. Fisetin, a GAMT inhibitor, shows potential for ccRCC treatment and can sensitize cells to axitinib.

Area of Science:

  • Oncology
  • Biochemistry
  • Molecular Biology

Background:

  • Clear cell renal cell carcinoma (ccRCC) is the most prevalent kidney cancer subtype.
  • Existing targeted therapies for ccRCC face challenges due to drug resistance, necessitating novel therapeutic targets.
  • The role of Guanidinoacetate N-methyltransferase (GAMT) in ccRCC pathogenesis is not well-defined.

Purpose of the Study:

  • To investigate the biological functions and molecular mechanisms of GAMT in ccRCC.
  • To identify potential therapeutic strategies targeting GAMT for ccRCC treatment.

Main Methods:

  • Analysis of GAMT expression in ccRCC tissues and cell lines.
  • In vitro and in vivo assays to assess GAMT's pro-oncogenic role.
  • Investigation of GAMT's interaction with p53.
  • Screening for and validation of GAMT inhibitors, including fisetin.
  • Evaluation of fisetin's efficacy in combination with axitinib.

Main Results:

  • GAMT is upregulated in ccRCC and correlates with poor prognosis.
  • GAMT promotes ccRCC development and progression independently of its enzymatic activity.
  • GAMT overexpression inhibits the tumor suppressor p53.
  • Fisetin was identified as a GAMT inhibitor that suppresses ccRCC progression.
  • Fisetin sensitizes ccRCC cells to axitinib in preclinical models.

Conclusions:

  • GAMT exhibits pro-oncogenic functions in ccRCC, potentially through non-enzymatic regulation of p53.
  • Fisetin represents a novel therapeutic agent for ccRCC, capable of inhibiting tumor progression and enhancing targeted therapy efficacy.
Keywords:
Clear cell renal cell carcinomaFisetinGAMTp53

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