Metformin: a case of divide and conquer

Abstract

Metformin is a widely prescribed anti-diabetic drug and its use is associated with lower cancer incidence. The mechanisms by which metformin attenuates tumorigenesis are not clearly understood. In a paper published in Proceedings of the National Academy of Sciences of the United States of America, Hirsch and colleagues show that metformin interferes with a signaling pathway, mediated by the transcription factor NF-κB, which drives cell transformation and is required for the maintenance of cancer stem cells.

Figure 1

Epithelial cancer cell inflammatory response. Treatment of cells expressing ER-Src with tamoxifen (see text) activates Src and elicits a transcriptional response, mediated by the transcription factor NF-κB, to drive the expression of Lin28, a miRNA binding protein. Lin28 binds to and attenuates the function of let-7 miRNAs, which normally control, among others, the translation of the cytokine IL-6. IL-6 is a potent activator of NF-κB, thereby providing a positive feedback that further amplifies the pathway [4]. In parallel, IL-6 activates another transcription factor, signal transducer and activator of transcription 3 (STAT3), to promote the expression of miR-21 and miR-181b-1, which inhibit the translation of the tumor suppressors PTEN and CYLD, respectively, further enhancing NF-κB activity [5]. Because NF-κB, STAT3 and IL-6 are also players in bona fide inflammatory responses elicited by immune cells, this signaling cascade is known as the inflammatory response or inflammatory feedback loop, alluding to the self-amplifying nature of the pathway.