Liraglutide Suppresses the Proliferation of Endometrial Cancer Cells Through the Adenosine 50-Monophosphate (AMP)-Activated Protein Kinase Signaling Pathway
Endometrial cancer (EC) is one of the most common gynecological malignancies, with progesterone-based hormone therapy serving as a cornerstone for conservative management in early-stage, progesterone receptor (PGR)-positive cases. However, progesterone resistance develops in approximately 25% of patients, highlighting the need for novel therapeutic strategies to enhance sensitivity to progesterone. Recent attention has turned to metabolic syndrome (MS), particularly obesity and type 2 diabetes mellitus (T2DM), which are established risk factors for EC. Liraglutide, a glucagon-like peptide-1 (GLP-1) analog widely used for managing T2DM and obesity, has shown emerging potential in cancer research. This study investigated liraglutide’s antiproliferative effects on EC cells, its synergy with progesterone, and its role in modulating PGR expression via the adenosine 50-monophosphate (AMP)-activated protein kinase (AMPK) signaling pathway.
Antiproliferative Effects of Liraglutide on Endometrial Cancer Cells
The study utilized two EC cell lines: Ishikawa (IK) and human endometrial carcinoma (HEC)-1B. Cells were plated in 96-well plates at densities of 8 × 10³ (IK) and 1 × 10⁴ (HEC-1B) cells per well. After serum starvation for 24 hours, cells were treated with increasing concentrations of liraglutide (0.1, 0.5, 1, 2, 5, and 10 mmol/L) for 24 hours. Cell viability was assessed using the cell counting kit-8 (CCK-8) assay, with absorbance measured at 450 nm.
Liraglutide exhibited time- and concentration-dependent growth inhibition in both cell lines. For IK cells, significant antiproliferative effects were observed at concentrations as low as 0.5 mmol/L, while HEC-1B cells required 1 mmol/L to achieve similar suppression. At higher concentrations (5 and 10 mmol/L), proliferation inhibition became markedly pronounced (P < 0.05). Prolonged exposure to liraglutide intensified these effects. Notably, IK cell proliferation declined progressively with 5 mmol/L liraglutide but plateaued at 10 mmol/L. In contrast, HEC-1B cells displayed a sharp decline in viability at concentrations ≥5 mmol/L over time, underscoring differential sensitivity between the two cell lines.
Synergistic Effects of Liraglutide and Medroxyprogesterone Acetate (MPA)
To evaluate combinatorial efficacy, cells were treated with liraglutide (1, 2, and 5 mmol/L) alongside medroxyprogesterone acetate (MPA; 0, 5, and 10 mmol/L) for 48 hours. The interaction between liraglutide and MPA was quantified using the combination index (CI), where CI < 1 indicates synergy.
Both agents alone significantly suppressed EC cell proliferation (P < 0.05). However, liraglutide synergized with MPA across all tested concentrations, producing CI values indicative of moderate to strong synergy (CI < 1). For instance, combining 1 mmol/L liraglutide with 5 mmol/L MPA yielded a more pronounced inhibition of proliferation compared to either agent alone (P < 0.05). This synergy suggests that liraglutide potentiates the antitumor effects of progesterone, offering a promising strategy to combat progesterone resistance.
Liraglutide Upregulates PGR Expression via AMPK Signaling
Given the critical role of PGR in progesterone sensitivity, the study explored liraglutide’s impact on PGR expression. Real-time reverse transcription-polymerase chain reaction (RT-PCR) revealed that liraglutide (1–5 mmol/L) significantly upregulated PGR mRNA levels in both IK and HEC-1B cells (P < 0.05). Maximal upregulation occurred at 1–2 mmol/L, with IK cells showing a 1.5-fold increase and HEC-1B cells a 2-fold increase compared to controls.
To elucidate the mechanism, cells were co-treated with liraglutide and Compound C, a selective AMPK inhibitor. Compound C partially reversed liraglutide-induced PGR upregulation, confirming AMPK’s role in modulating PGR expression. Western blot analysis further demonstrated that liraglutide increased phosphorylated AMPK (p-AMPK) protein levels while suppressing phosphorylated p70S6 kinase (p-P70S6K), a downstream mTOR effector involved in cell growth. These changes were blunted by Compound C, establishing AMPK activation as a key mediator of liraglutide’s effects.
AMPK Signaling Drives Antiproliferative and Progesterone-Sensitizing Effects
The AMPK pathway serves as a cellular energy sensor, inhibiting anabolic processes like protein synthesis via mTOR/p70S6K. Liraglutide’s activation of AMPK (evidenced by elevated p-AMPK) and subsequent suppression of p-P70S6K align with its antiproliferative effects. By downregulating p-P70S6K, liraglutide likely curtails ribosomal biogenesis and protein synthesis, thereby impeding cancer cell growth.
Moreover, AMPK’s regulation of PGR expression provides a dual therapeutic benefit: enhanced progesterone sensitivity complements direct antiproliferative activity. This mechanism is particularly relevant in EC, where PGR loss correlates with aggressive disease and hormone resistance.
Implications for Clinical Practice
Progesterone remains a first-line therapy for early-stage EC, but resistance poses a significant challenge. This study positions liraglutide as an adjunctive agent capable of reversing progesterone resistance through PGR upregulation and AMPK activation. Given liraglutide’s established safety profile in diabetes and obesity management, repurposing it for EC therapy could offer a low-risk, high-reward strategy.
Furthermore, the synergy between liraglutide and MPA suggests that lower doses of each agent may achieve therapeutic efficacy, minimizing side effects. Future clinical trials should validate these findings in vivo and explore optimal dosing regimens.
Conclusion
This study demonstrates that liraglutide suppresses endometrial cancer cell proliferation through AMPK-mediated pathways, enhances progesterone sensitivity by upregulating PGR, and synergizes with MPA to amplify antitumor effects. These findings highlight liraglutide’s potential as a novel therapeutic agent in EC, particularly for patients with progesterone resistance or comorbid metabolic conditions. By targeting energy-sensing pathways and hormone receptor expression, liraglutide offers a multifaceted approach to EC management, bridging metabolic and oncological therapeutics.
doi.org/10.1097/CM9.0000000000001363
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