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PKM1 is involved in resistance to anti-cancer drugs

Kohei Taniguchi1, Miku Sakai2, Nobuhiko Sugito2

  • 1United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan; Department of General and Gastroenterological Surgery, Osaka Medical College, Daigaku-machi, Takatsuki, Osaka 569-8686, Japan.

Biochemical and Biophysical Research Communications
|March 26, 2016
PubMed

Insights

Pyruvate kinase muscle 1 (PKM1) promotes chemoresistance by enhancing oxidative phosphorylation. Silencing PKM1 induces apoptosis and restores sensitivity to chemotherapy in resistant cancer cells.

Area of Science:

  • Oncology
  • Cancer Metabolism
  • Molecular Biology

Background:

  • Chemotherapy resistance remains a significant clinical challenge.
  • Understanding chemoresistance mechanisms is vital for effective cancer treatment.
  • Cancer-specific metabolism, including the Warburg effect, plays a role in chemoresistance.

Purpose of the Study:

  • To investigate the role of cancer metabolism-related genes, specifically pyruvate kinase muscle (PKM) isoforms, in chemoresistance.
  • To elucidate the function of PKM1 in the development of resistance to 5-fluorouracil (5-FU) and oxaliplatin.
  • To explore PKM1 as a potential therapeutic target for overcoming chemoresistance.

Main Methods:

  • Analysis of PKM isoform expression in chemoresistant cell lines.
  • Overexpression and gene-silencing (siRNA) of PKM1 in DLD-1 cells (parental, 5-FU-resistant, oxaliplatin-resistant).
  • Assessment of apoptosis induction, mitochondrial membrane potential, and response to combination therapy.

Main Results:

  • PKM1 was commonly upregulated in various chemoresistant cells and promoted resistance to 5-FU and oxaliplatin.
  • PKM1 overexpression increased resistance in parental DLD-1 cells.
  • PKM1 gene silencing induced apoptosis in both parental and resistant cells by decreasing mitochondrial membrane potential.
  • Combination therapy with 5-FU or oxaliplatin and siR-PKM1 was effective against resistant cells.

Conclusions:

  • PKM1 upregulation is a key mechanism driving chemoresistance by promoting oxidative phosphorylation.
  • Targeting PKM1, through gene silencing, can overcome chemoresistance and re-sensitize cancer cells to chemotherapy.
  • PKM1 represents a promising therapeutic target for developing novel strategies to combat chemoresistance by modulating cancer energy metabolism.
Keywords:
Anti-cancer drugChemoresistancePKM1PKM2Warburg effect

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