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Knockdown of LKB1 Sensitizes Endometrial Cancer Cells via AMPK Activation

Seung Bae Rho1, Hyun Jung Byun2, Boh-Ram Kim2

  • 1Division of Translational Science, Research Institute, National Cancer Center, Goyang 10408, Republic of Korea.

Biomolecules & Therapeutics
|October 5, 2021
PubMed

Insights

Metformin triggers apoptosis in HeLa cervical cancer cells by activating AMPK and requires the LKB1 gene. This mechanism was not observed in endometrial cancer cells lacking LKB1 expression.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Metformin, an anti-diabetic drug, exhibits anticancer properties.
  • Its precise molecular mechanisms in tumorigenesis, particularly in endometrial cancer, remain unclear.
  • Previous research suggests metformin inhibits cell proliferation and induces apoptosis.

Purpose of the Study:

  • To investigate the effects of metformin on cell viability and apoptosis in cervical (HeLa) and endometrial (HEC-1-A, KLE) cancer cells.
  • To elucidate the molecular signaling pathways involved in metformin's anti-cancer effects.
  • To determine the role of Liver Kinase B1 (LKB1) in mediating metformin's actions.

Main Methods:

  • Cell viability and apoptosis assays were performed on cancer cell lines treated with metformin.
  • Promoter activity assays for p27, p21, Bcl-2, and IL-6 were conducted.
  • Western blotting was used to assess the phosphorylation status of mTOR, p70S6K, and 4E-BP1, and AMPK activation.
  • LKB1 gene expression was analyzed, and its role was further investigated through overexpression and knockdown experiments.

Main Results:

  • Metformin suppressed growth and induced apoptosis in HeLa cells, but not in HEC-1-A and KLE cells.
  • Metformin enhanced p27 and p21 promoter activity while reducing Bcl-2 and IL-6 activity in HeLa cells.
  • Metformin activated AMPK, leading to decreased mTOR/p70S6K/4E-BP1 phosphorylation in HeLa cells.
  • LKB1 gene expression was detected in HeLa cells but not in endometrial cancer cells.
  • LKB1 overexpression inhibited metformin-induced apoptosis in HeLa cells, while LKB1 knockdown enhanced apoptosis in HEC-1-A and KLE cells.

Conclusions:

  • Metformin's anti-proliferative and apoptotic effects are dependent on the presence of the LKB1 gene.
  • LKB1 mediates metformin-induced apoptosis via AMPK activation in cancer cells.
  • These findings reveal a specific molecular mechanism for metformin's action in tumorigenesis, highlighting LKB1 as a key factor.
Keywords:
AMPKApoptosisEndometrial cancerHeLaLKB1Metformin

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