Metformin Influence on Cancer Progression in Diabetic Patients

Metformin, a first‐line therapy for type 2 diabetes, has been consistently associated with reduced cancer incidence and improved outcomes in diabetic cohorts. Large retrospective studies suggest that long‐term metformin use attenuates the risk of tumours of the breast, colon, liver and head and neck, with the greatest benefit seen after two years of continuous therapy. Mechanistic investigations reveal that metformin activates the AMP‐activated protein kinase pathway, leading to inhibition of mTOR complex 1, downregulation of cyclin D1 and suppression of protein synthesis. By lowering circulating insulin and insulin‐like growth factor levels, metformin may also deprive insulin-responsive cancers of a key proliferative stimulus. Emerging evidence implicates metformin in modulation of the tumour microenvironment, enhancing T-cell infiltration and sensitising cancer cells to chemoradiotherapy. These multifaceted actions underscore metformin’s potential as a repurposed adjuvant in oncology, with applications ranging from chemoprevention in high-risk diabetic patients to combination strategies that exploit metabolic vulnerabilities in established tumours.

Research from Nature Portfolio

Two seminal studies have delineated how metformin modulates metabolic signalling in squamous cell carcinomas. One investigation demonstrated that metformin disrupts a Late SV40 Factor–Aurora-A axis, reducing cell proliferation and metastatic behaviour in oral cancer models. In vitro and xenograft experiments showed that metformin treatment led to decreased expression of both Aurora-A kinase and its transcriptional regulator LSF, resulting in reduced tumour growth and invasion. A complementary study explored the combination of metformin with a glutaminase 1 inhibitor in head and neck carcinoma cells. By concurrently limiting glucose and glutamine metabolism, this dual-metabolic blockade induced synergistic cell cycle arrest and apoptosis, pointing to a therapeutic strategy that targets two major nutrient pathways simultaneously. Collectively, these Nature-published works highlight metformin’s capacity to reprogramme cancer cell metabolism and to cooperate with other agents in suppressing tumour progression.

Metformin Influence on Cancer Progression in Diabetic Patients publication trend

The graph below shows the total number of articles in metformin influence on cancer progression in diabetic patients across all publications each year (not limited to Nature Index journals).

Technical terms

AMP-activated protein kinase (AMPK): A cellular energy sensor that, when activated by metformin, inhibits anabolic processes and mTOR complex 1 to conserve energy.

mTOR complex 1 (mTORC1): A signalling hub controlling protein synthesis and cell growth; its inhibition is central to metformin’s antiproliferative effect.

Epidermal growth factor receptor (EGFR): A transmembrane tyrosine kinase whose overexpression drives proliferation in many carcinomas.

Apoptosis: Programmed cell death characterised by caspase activation and DNA fragmentation; enhanced by metformin in several cancer models.

Ubiquitination: A post-translational modification tagging proteins for proteasomal degradation, implicated in metformin-induced downregulation of oncogenic factors.

References

1. Metformin may reduce oral cancer risk in patients with type 2 diabetes. Oncotarget (2015).
2. Metformin disrupts malignant behavior of oral squamous cell carcinoma via a novel signaling involving Late SV40 factor/Aurora-A. Scientific Reports (2017).
3. Targeting cellular metabolism to reduce head and neck cancer growth. Scientific Reports (2019).
4. Diabetes and its Potential Impact on Head and Neck Oncogenesis. Journal of Cancer (2020).
5. The effect of metformin use on hypopharyngeal squamous cell carcinoma in diabetes mellitus patients. BMC Cancer (2019).
6. Metformin Downregulates the Expression of Epidermal Growth Factor Receptor Independent of Lowering Blood Glucose in Oral Squamous Cell Carcinoma. Frontiers in Endocrinology (2022).