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1-Pyrroline-5-carboxylate inhibit T cell glycolysis in prostate cancer microenvironment by SHP1/PKM2/LDHB axis

Lei Chang1, Guohao Li2, Shan Jiang3

  • 1Department of Urology, Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430014, China. changlei1025@163.com.

Cell Communication and Signaling : CCS
|February 7, 2024
PubMed
Abstract

Insights

Prostate cancer cells release 1-Pyrroline-5-carboxylate (P5C), which inhibits T cell glycolysis via SHP1/PKM2/LDHB. An antibody targeting P5C restores T cell function and inhibits tumor growth.

Area of Science:

  • Immunology
  • Metabolic pathways
  • Cancer biology

Background:

  • Prostate cancer cells release 1-Pyrroline-5-carboxylate (P5C).
  • P5C inhibits T cell proliferation and function by increasing SHP1 expression.
  • The impact of P5C on T cell metabolism requires further investigation.

Purpose of the Study:

  • To explore the influence of P5C on T cell metabolism.
  • To develop an antibody targeting P5C to restore T cell functions.
  • To elucidate the molecular mechanisms underlying P5C-mediated T cell suppression.

Main Methods:

  • Co-immunoprecipitation and liquid chromatography mass spectrometry (LC/MS-MS) to identify SHP1-binding proteins and analyze T cell metabolism.
  • Seahorse XF96 analyzer to assess T cell glycolysis.
  • Monoclonal antibody production for P5C targeting and in vitro/in vivo functional validation.

Main Results:

  • PKM2 and LDHB bind to SHP1 in T cells; P5C increases p-PKM2 levels but not PKM2 or LDHB.
  • P5C inhibits T cell glycolysis, reduces intracellular lactic acid, and affects energy/carbohydrate metabolism.
  • A P5C-targeting antibody restored T cell glycolysis and function, and inhibited prostate tumor growth in vivo.

Conclusions:

  • P5C inhibits T cell glycolysis by targeting SHP1/PKM2/LDHB complexes.
  • Targeting P5C with an antibody can restore T cell function and suppress prostate tumor growth.
  • This highlights a novel mechanism of immune suppression in prostate cancer and a potential therapeutic strategy.
Keywords:
GlycolysisP5CProstate cancerSHP1T cell

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