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Metformin Regulates the Expression of CD133 Through the AMPK-CEBPβ Pathway in Hepatocellular Carcinoma Cell Lines

Osamu Maehara1, Shunsuke Ohnishi2, Ayaka Asano1

  • 1Department of Pathophysiology and Therapeutics, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.

Neoplasia (New York, N.Y.)
|May 3, 2019
PubMed

Insights

Metformin reduces cancer stem cell marker CD133 by activating AMPK signaling, which influences CEBPβ isoforms. This pathway offers a new strategy for targeting cancer stem cells (CSCs) and improving treatments.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • CD133 is a cancer stem cell marker targeted for cancer therapy.
  • Metformin, an anti-diabetic drug, reduces cancer risk and cancer stem-like cells (CSCs), including CD133 expression.
  • The mechanism by which metformin reduces CD133 expression remains unclear.

Purpose of the Study:

  • To elucidate the molecular mechanism by which metformin suppresses CD133 expression.
  • To investigate the role of adenosine monophosphate (AMP)-activated protein kinase (AMPK) and CCAAT/enhancer-binding protein beta (CEBPβ) in metformin's effect on CD133.

Main Methods:

  • Investigated metformin's effect on CD133 promoter activity via AMPK and mammalian target of rapamycin (mTOR) signaling.
  • Analyzed the role of CEBPβ isoforms (LAP and LIP) in regulating CD133 expression.
  • Utilized 3D culture and drug sensitivity assays to assess the functional impact of CEBPβ isoforms and metformin treatment.

Main Results:

  • Metformin suppressed CD133 expression primarily through the CD133 P1 promoter via AMPK signaling.
  • AMPK inhibition reversed the metformin-induced reduction in CD133.
  • Metformin upregulated CEBPβ, with the LAP isoform increasing CD133 expression and the LIP isoform suppressing it.
  • LAP-overexpressing cells showed increased spheroid formation and 5-fluorouracil (5-FU) resistance, while LIP-overexpressing cells were more sensitive to 5-FU and showed synergistic effects with metformin.

Conclusions:

  • Metformin-AMPK-CEBPβ signaling is critical for regulating CD133 gene expression.
  • Modulating the LAP/LIP ratio presents a potential novel therapeutic strategy for targeting CSCs in cancer treatment.

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