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Nuclear PTEN Regulates Thymidylate Biosynthesis in Human Prostate Cancer Cell Lines

Zoe N Loh1,2, Mu-En Wang1,2, Changxin Wan3

  • 1Department of Pathology, Duke University School of Medicine, Durham, NC 27710, USA.

Metabolites
|August 25, 2023
PubMed

Insights

Nuclear PTEN regulates pyrimidine metabolism, specifically thymidylate (dTMP) biosynthesis, by interacting with MTHFD1. This finding reveals a novel nuclear role for PTEN in metabolic control.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Metabolic Regulation

Background:

  • The tumor suppressor PTEN (phosphatase and tensin homologue deleted on chromosome 10) is crucial for cellular processes, including metabolism.
  • PTEN's role in the cytosol involves lipid phosphatase activity regulating the PI3K/AKT/mTORC1 pathway.
  • PTEN's metabolic functions within the nucleus are not well understood.

Purpose of the Study:

  • To investigate the nuclear functions of PTEN in metabolic regulation.
  • To determine PTEN's role in pyrimidine metabolism, particularly de novo thymidylate (dTMP) biosynthesis.

Main Methods:

  • Utilized a gain-of-function strategy to specifically target PTEN to the plasma membrane and nucleus.
  • Investigated PTEN's interactions with key enzymes involved in nucleotide biosynthesis.

Main Results:

  • Demonstrated that nuclear PTEN significantly contributes to de novo thymidylate (dTMP) biosynthesis.
  • Identified an interaction between PTEN and methylenetetrahydrofolate dehydrogenase 1 (MTHFD1), a critical enzyme in folate metabolism.
  • Showed that PTEN influences the production of 5,10-methylenetetrahydrofolate, a cofactor essential for thymidylate synthase (TYMS).

Conclusions:

  • PTEN possesses a previously unrecognized nuclear function in regulating dTMP biosynthesis.
  • This nuclear role of PTEN in pyrimidine metabolism has potential implications for cancer therapy, particularly for prostate cancer cells with nuclear-excluded PTEN.
Keywords:
cancermetabolic compartmentalizationnuclear PTENthymidylate biosynthesis

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