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Mechanism of Kemeng Fang's Inhibition of Podocyte Apoptosis in Rats with Membranous Nephropathy through the PI3K/AKT Signaling Pathway
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Novel Specific Pyruvate Kinase M2 Inhibitor, Compound 3h, Induces Apoptosis and Autophagy through Suppressing

Chunxue Jiang1, Xiaodi Zhao2, Taejoo Jeong1

  • 1School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea.

Cancers
|January 8, 2023
PubMed

Insights

A novel Pyruvate kinase M2 (PKM2) inhibitor, compound 3h, demonstrates potent anticancer effects in prostate cancer cells by targeting glycolysis and inducing cell death. This discovery offers a new strategy for PKM2-overexpressed cancer therapy.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • Pyruvate kinase M2 (PKM2) is a key glycolytic enzyme overexpressed in many cancers.
  • The role of PKM2 in cancer chemotherapy is not fully understood.
  • Targeting cancer cell metabolism is a promising therapeutic strategy.

Purpose of the Study:

  • To investigate the anticancer activity of a novel PKM2 inhibitor, compound 3h, in prostate cancer cells.
  • To elucidate the effects of compound 3h on cell metabolism and associated signaling pathways.
  • To evaluate the binding affinity of compound 3h to PKM2.

Main Methods:

  • Molecular docking to assess compound-protein interactions.
  • Enzyme activity and expression assays for PKM2.
  • Cytotoxicity, colony formation, apoptosis, and autophagy assays.
  • Analysis of extracellular acidification rate (ECAR) and oxygen consumption rate (OCR).
  • Western blotting to examine AMPK and mTOR/p70S6K pathway activation.

Main Results:

  • Compound 3h showed higher binding affinity to PKM2 than compound 3K.
  • Compound 3h significantly inhibited PKM2 activity and expression.
  • Compound 3h exhibited potent anticancer activity against LNCaP cells, inducing apoptosis and autophagy.
  • Compound 3h activated AMPK and inhibited the mTOR/p70S6K pathway.
  • Compound 3h suppressed glycolysis and mitochondrial respiration.

Conclusions:

  • Compound 3h effectively inhibits prostate cancer cell metabolism, leading to apoptotic and autophagic cell death.
  • Targeting PKM2 with specific inhibitors represents a viable therapeutic approach for PKM2-overexpressed prostate cancers.
  • Compound 3h holds potential as an anticancer agent by modulating cancer cell metabolism.
Keywords:
PKM2 inhibitorsapoptosiscell metabolismglycolysisprostate cancer

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