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Metformin promotes anticancer activity of NK cells in a p38 MAPK dependent manner
Wenjiao Xia1, Xin Qi1, Mingfeng Li1
1Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, P. R. China.
Abstract:
Metformin, a drug prescribed to treat type 2 diabetes, has been reported to possess antitumor activity via immunity activation. However, the influence of metformin on natural killer (NK) cells is not fully understood. Here, we investigated whether metformin exerts a potent anticancer effect by activating NK cells. The results showed that sustained exposure to metformin enhances the cytolytic activity of NK-92 cells. Moreover, this enhancement of cytotoxicity by metformin was also observed in NK cells from healthy peripheral blood and cancer patient ascites. Mechanistically, metformin induced activation of the JAK1/2/3/STAT5 and AKT/mTOR pathways in a p38 MAPK-dependent manner rather than an AMPK-dependent manner. In vivo experiments, metformin also improved cancer surveillance of NK cells in mouse models of lymphoma clearance and metastatic melanoma. Additionally, combination treatment with metformin and anti-PD-1 antibodies increased the therapy response rates of B16F10 melanoma. Moreover, metformin treatment increased NK cell and T cell infiltration in tumors. Therefore, these results provide a deeper understanding of metformin on the effector function of NK cells and will contribute to the development and applications of metformin in cancer treatment strategies.
Insights
Metformin enhances natural killer (NK) cell activity, boosting the immune system's ability to fight cancer. This finding supports metformin's potential as a novel cancer therapy by improving NK cell-mediated tumor cell killing.
Area of Science:
- Immunology
- Pharmacology
- Oncology
Background:
- Metformin, a type 2 diabetes drug, shows potential antitumor effects through immune activation.
- The specific impact of metformin on natural killer (NK) cells remains unclear.
Purpose of the Study:
- To investigate metformin's role in activating NK cells for cancer treatment.
- To elucidate the mechanisms behind metformin-induced NK cell enhancement.
Main Methods:
- Assessed NK-92 cell line and primary NK cells' cytolytic activity upon metformin exposure.
- Analyzed intracellular signaling pathways (JAK/STAT, AKT/mTOR, p38 MAPK, AMPK) using western blotting.
- Evaluated metformin's efficacy in vivo using mouse models for lymphoma and melanoma.
- Examined the combination therapy of metformin with anti-PD-1 antibodies in melanoma models.
Main Results:
- Metformin significantly enhanced NK cell-mediated cytotoxicity in vitro.
- Metformin activated JAK/STAT and AKT/mTOR pathways in a p38 MAPK-dependent manner.
- In vivo studies demonstrated improved NK cell cancer surveillance and tumor infiltration.
- Combination therapy with anti-PD-1 antibodies improved melanoma treatment response.
Conclusions:
- Metformin potentiates NK cell effector functions, offering a new avenue for cancer immunotherapy.
- Metformin's mechanism involves specific signaling pathway activation, distinct from AMPK.
- Findings support metformin's development as an adjunct cancer therapy to enhance immune responses.
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