Metformin elicits anticancer effects through the sequential modulation of DICER and c-MYC

Abstract

Diabetic patients treated with metformin have a reduced incidence of cancer and cancerrelated mortality. Here we show that metformin affects engraftment and growth of breast cancer tumours in mice. This correlates with the induction of metabolic changes compatible with clear anticancer effects. We demonstrate that microRnA modulation underlies the anticancer metabolic actions of metformin. In fact, metformin induces DICER expression and its effects are severely impaired in DICER knocked down cells. Conversely, ectopic expression of DICER recapitulates the effects of metformin in vivo and in vitro. The microRnAs upregulated by metformin belong mainly to energy metabolism pathways. Among the messenger RnAs downregulated by metformin, we found c-mYC, IRs-2 and HIF1alpha. Downregulation of c-mYC requires AmP-activated protein kinase-signalling and mir33a upregulation by metformin. Ectopic expression of c-mYC attenuates the anticancer metabolic effects of metformin. We suggest that DICER modulation, mir33a upregulation and c-mYC targeting have an important role in the anticancer metabolic effects of metformin.

Metformin‐mediated increase in DICER1 regulates microRNA expression and cellular senescence

“…Given that metformin elevates DICER1 in cultured cancer cells (Blandino et al ., 2012), we wanted to examine whether changes in DICER1 expression occur in mice chronically treated with metformin and to compare these findings with those of mice on dietary caloric restriction, an intervention that extends lifespan in mice. In response to metformin and dietary caloric restriction, there is an upregulation in Dicer1 mRNA levels in the livers of treated mice compared with control mice on standard diet (Fig.…”

“…As DICER1 also plays other important roles in the RNA‐induced silencing complex (RISC) and in RNA metabolism (Burger & Gullerova, 2015), we cannot exclude the possibility that these other functions of DICER1 may be altered by metformin and contribute to metformin signaling. In addition, upregulation of DICER1 by metformin may also be regulated, in part, at the transcriptional level (Blandino et al ., 2012); a comprehensive view of the spectrum of DICER1 functions influenced by metformin is beyond the scope of this investigation.…”

“…Although many studies have focused on uncovering how metformin elicits anticancer effects, the exact mechanism of tumor inhibition remains unknown (Foretz et al ., 2014). Studies using cancer cells in culture and murine tumor xenografts have found that metformin inhibits tumorigenesis by upregulating DICER1 (Blandino et al ., 2012), a key enzyme that processes microRNAs (miRNAs). Therefore, it is possible that upregulation of DICER1 may in part mediate metformin's antitumorigenic effects.…”

Extracellular acidity strengthens mesenchymal stem cells to promote melanoma progression

“…38 Then, it was demonstrated that stromal cells may perform aerobic glycolysis under the influence of tumor cells and donate lactate to feed OxPhos metabolism of tumor cells, the so-called "Reverse Warburg Effect." [39][40][41] Metformin, a drug that is found to be effective in tumors, [42][43][44][45] when it was added in acidic medium, which will be used for MSC conditioning, blocks TGFb expression and reverts inhibition of GLUT 1 and 3 elicited by acidic medium in MSC. Moreover, melanoma cells conditioned by LpH-metformin-treated MSC medium exhibited a reconstituted epithelial-like profile and a reduced invasion, that were associated with a reduction of GLUT 1, 3.…”

miRNAs link metabolic reprogramming to oncogenesis

“…As a result antidiabetic drugs such as metformin, which is currently taken by 100 million people worldwide, are being explored for anti-tumor activity [144][145][146]. Multiple epidemiological studies show that diabetic patients treated with metformin have reduced incidence of cancer and reduced cancer mortality [145].…”