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Metformin Reverses Progesterone Resistance in Endometrial Cancer by Targeting the AMPK-FOXO1-CALB2 Pathway
Liangli Hong1, Ruilin Lin1, Weifeng Zhang2
1Department of Pathology, The First Affiliated Hospital of Shantou University Medical College, Shantou City, Guangdong Province, 515041, China.
Introduction:
Progesterone therapy is standard for fertility-preserving endometrial cancer (ECC) patients, but primary and secondary resistance limit its efficacy. Metformin (MET) combined with progesterone shows promise, yet the synergistic mechanism remains unclear.
Materials And Methods:
In vitro cellular studies and nude mouse xenograft models were used. Cell proliferation, migration, and apoptosis were assessed by CCK8, flow cytometry, Western blot, and immunofluorescence. RNA sequencing and cell transfection verified that Forkhead box protein O1(FOXO1) inhibits ECC cell proliferation by downregulating Calbindin2 (CALB2). Xenograft models confirmed FOXO1's inhibitory role.
Results:
MET combined with Megestrol acetate (MPA) inhibited the proliferation of ECC cells and induced cell apoptosis, and its effect was stronger than that of a single drug. MET promoted FOXO1 nuclear localization. FOXO1 suppressed ECC cell proliferation and migration in vitro and in vivo. MET inhibited proliferation via FOXO1-dependent CALB2 downregulation. Both MET treatment and CALB2 knockdown caused mitochondrial Ca2+ overload, membrane potential depolarization, and apoptosis, effects that were reversed by FOXO1 knockdown or CALB2 overexpression.
Discussion:
MET with MPA inhibits proliferation and induces apoptosis in MPA-sensitive and resistant ECC cells. MET facilitates FOXO1 nuclear localization via adenosine monophosphate-activated protein kinase (AMPK) activation and AKT serine/threonine kinase 1 (Akt) inhibition. CALB2 is a key downstream target of nuclear FOXO1. The AMPK-FOXO1-CALB2 axis may represent a novel pathway activated by MET, inhibiting ECC proliferation and MPA resistance.
Conclusion:
The AMPK-FOXO1-CALB2 axis mediates MET-induced mitochondrial dysfunction and apoptosis, providing a mechanistic basis for MET to overcome progesterone resistance in ECC.
Insights
Metformin combined with progesterone therapy overcomes endometrial cancer resistance by activating the AMPK-FOXO1-CALB2 pathway, inducing apoptosis and inhibiting proliferation.
Area of Science:
- Gynecologic Oncology
- Molecular Mechanisms of Cancer
- Pharmacology
Background:
- Progesterone therapy is standard for endometrial cancer (ECC) but faces resistance.
- Metformin (MET) combined with progesterone shows promise, but its mechanism is unclear.
Purpose of the Study:
- To elucidate the synergistic mechanism of Metformin (MET) and progesterone in endometrial cancer (ECC).
- To investigate the role of the AMPK-FOXO1-CALB2 axis in MET's efficacy against ECC.
Main Methods:
- In vitro cellular studies and nude mouse xenograft models were employed.
- Assessed cell proliferation, migration, and apoptosis using CCK8, flow cytometry, Western blot, and immunofluorescence.
- RNA sequencing identified the FOXO1-CALB2 pathway; xenograft models confirmed FOXO1's inhibitory role.
Main Results:
- MET combined with Megestrol acetate (MPA) significantly inhibited ECC cell proliferation and induced apoptosis, outperforming single-drug treatment.
- MET promoted FOXO1 nuclear localization via AMPK activation and Akt inhibition, leading to CALB2 downregulation.
- MET-induced mitochondrial dysfunction and apoptosis were mediated by the AMPK-FOXO1-CALB2 axis.
Conclusions:
- The AMPK-FOXO1-CALB2 axis is a novel pathway activated by MET, inhibiting ECC proliferation and overcoming progesterone resistance.
- MET with MPA demonstrates efficacy in both progesterone-sensitive and resistant ECC.
- This study provides a mechanistic basis for using MET to enhance progesterone therapy in ECC.
