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The biguanide drug metformin is widely used in type 2 diabetes mellitus therapy, due to its ability to decrease serum glucose levels, mainly by reducing hepatic gluconeogenesis and glycogenolysis. A considerable number of studies have shown that metformin, besides its antidiabetic action, can improve other disease states, such as polycystic ovary disease, acute kidney injury, neurological disorders, cognitive impairment and renal damage. In addition, metformin is well known to suppress the growth and progression of different types of cancer cells both in vitro and in vivo. Accordingly, several epidemiological studies suggest that metformin is capable of lowering cancer risk and reducing the rate of cancer deaths among diabetic patients. The antitumoral effects of metformin have been proposed to be mainly mediated by the activation of the AMP-activated protein kinase (AMPK). However, a number of signaling pathways, both dependent and independent of AMPK activation, have been reported to be involved in metformin antitumoral action. Among these, the Wingless and Int signaling pathway have recently been included. Here, we will focus our attention on the main molecular mechanisms involved.

Multiple lines of evidence suggest that metformin, an antidiabetic drug, exerts anti-tumorigenic effects in different types of cancer. Metformin has been reported to affect cancer cells’ metabolism and proliferation mainly through the activation of AMP-activated protein kinase (AMPK). Here, we show that metformin inhibits, indeed, endometrial cancer cells’ growth and induces apoptosis. More importantly, we report that metformin affects two important pro-survival pathways, such as the Unfolded Protein Response (UPR), following endoplasmic reticulum stress, and the WNT/β-catenin pathway. GRP78, a key protein in the pro-survival arm of the UPR, was indeed downregulated, while GADD153/CHOP, a transcription factor that mediates the pro-apoptotic response of the UPR, was upregulated at both the mRNA and protein level. Furthermore, metformin dramatically inhibited β-catenin mRNA and protein expression. This was paralleled by a reduction in β-catenin transcriptional activity, since metformin inhibited the activity of a TCF/LEF-luciferase promoter. Intriguingly, compound C, a well-known inhibitor of AMPK, was unable to prevent all these effects, suggesting that metformin might inhibit endometrial cancer cells’ growth and survival through the modulation of specific branches of the UPR and the inhibition of the Wnt/β-catenin pathway in an AMPK-independent manner. Our findings may provide new insights on the mechanisms of action of metformin and refine the use of this drug in the treatment of endometrial cancer.

Adipose-derived stem cells (ADSCs) play a crucial role in angiogenesis and repair of damaged tissues. However, in pathological conditions including diabetes, ADSC function is compromised. This work aims at evaluating the effect of Methylglyoxal (MGO), a product of chronic hyperglycemia, on mouse ADSCs’ (mADSCs) pro-angiogenic function and the molecular mediators involved. The mADSCs were isolated from C57bl6 mice. MGO-adducts and p-p38 MAPK protein levels were evaluated by Western Blot. Human retinal endothelial cell (hREC) migration was analyzed by transwell assays. Gene expression was measured by qRT-PCR, and SA-βGal activity by cytofluorimetry. Soluble factor release was evaluated by multiplex assay. MGO treatment does not impair mADSC viability and induces MGO-adduct accumulation. hREC migration is reduced in response to both MGO-treated mADSCs and conditioned media from MGO-treated mADSCs, compared to untreated cells. This is associated with an increase of SA-βGal activity, SASP factor release and p53 and p21 expression, together with a VEGF- and PDGF-reduced release from MGO-treated mADSCs and a reduced p38-MAPK activation in hRECs. The MGO-induced impairment of mADSC function is reverted by senolytics. In conclusion, MGO impairs mADSCs’ pro-angiogenic function through the induction of a senescent phenotype, associated with the reduced secretion of growth factors crucial for hREC migration.