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Metformin increases sensitivity of osteosarcoma stem cells to cisplatin by inhibiting expression of PKM2

Depeng Shang1, Ju Wu2, Lianyi Guo3

  • 1Department of Orthopedics, Zhongshan Hospital Affiliated of Dalian University, Dalian, Liaoning 116001, P.R. China.

International Journal of Oncology
|April 11, 2017
PubMed

Insights

Metformin reverses cisplatin resistance in osteosarcoma stem cells by downregulating pyruvate kinase M2 (PKM2). This strategy enhances chemotherapy effectiveness and promotes cancer cell death.

Area of Science:

  • Oncology
  • Cancer Biology
  • Pharmacology

Background:

  • Multiple drug resistance is a significant challenge in osteosarcoma (OS) treatment.
  • Cancer stem cells (CSCs) are implicated in chemoresistance and are potential therapeutic targets.

Purpose of the Study:

  • To investigate cisplatin sensitivity in OS stem cells versus non-stem cells.
  • To elucidate the role of pyruvate kinase M2 (PKM2) in chemoresistance.
  • To evaluate metformin as a strategy to overcome cisplatin resistance in OS stem cells.

Main Methods:

  • Comparison of cisplatin sensitivity between OS stem cells and non-stem cells.
  • Investigation of PKM2 expression in OS stem cells.
  • Assessment of metformin's effect on cisplatin IC50 and PKM2 expression.
  • Analysis of glucose uptake, lactate, ATP production, and apoptosis in response to metformin and cisplatin.

Main Results:

  • OS stem cells exhibited significantly higher cisplatin resistance than non-stem cells.
  • Overexpression of PKM2 was identified as the mechanism driving cisplatin resistance in OS stem cells.
  • Metformin co-treatment decreased cisplatin's IC50 in HOS OS stem cells by downregulating PKM2.
  • Metformin inhibited glucose uptake, lactate, and ATP production, enhancing cisplatin-induced apoptosis and overcoming resistance.

Conclusions:

  • PKM2 is crucial for cisplatin resistance in osteosarcoma stem cells.
  • Metformin effectively sensitizes OS stem cells to cisplatin by targeting PKM2 and altering cellular metabolism.
  • Metformin enhances the efficacy of various chemotherapeutic agents against OS stem cells.

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