Limits...
Metformin: a case of divide and conquer.

Anastasiou D - Breast Cancer Res. (2013)

Bottom Line: 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.

View Article: PubMed Central - HTML - PubMed

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.

Show MeSH

Related in: MedlinePlus

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.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3672665&req=5

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.

Mentions: An experimental model that has proven fruitful in elucidating the molecular characteristics of CSCs employs immortalized mammary epithelial cells engineered to express a fusion of the oncogene v-Src (a tyrosine kinase) with the ligand-binding domain of the estrogen receptor (ER). Addition of the synthetic ER ligand tamoxifen induces dimerization of the ER-Src fusion, leading to activation of Src by trans-phosphorylation. Treatment of cells expressing ER-Src with tamoxifen elicits a signaling cascade, referred to as the inflammatory response or inflammatory feedback loop, that is mediated by the transcription factor NF-κB and its downstream target cytokine IL-6 (Figure 1) [4,5]. Activation of the inflammatory response is essential for Src-induced transformation of mammary epithelial cells, and the cells' ability to form tumors is impeded when this pathway is blocked. Furthermore, Src activation promotes the expansion of the CSC population and CSCs have enhanced activity of the inflammatory pathway compared with non-CSCs. CSCs are therefore likely to exhibit increased dependence on the inflammatory feedback loop, and pharmacological interference with this pathway may limit their tumorigenic potential.


Metformin: a case of divide and conquer.

Anastasiou D - Breast Cancer Res. (2013)

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.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3672665&req=5

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.
Mentions: An experimental model that has proven fruitful in elucidating the molecular characteristics of CSCs employs immortalized mammary epithelial cells engineered to express a fusion of the oncogene v-Src (a tyrosine kinase) with the ligand-binding domain of the estrogen receptor (ER). Addition of the synthetic ER ligand tamoxifen induces dimerization of the ER-Src fusion, leading to activation of Src by trans-phosphorylation. Treatment of cells expressing ER-Src with tamoxifen elicits a signaling cascade, referred to as the inflammatory response or inflammatory feedback loop, that is mediated by the transcription factor NF-κB and its downstream target cytokine IL-6 (Figure 1) [4,5]. Activation of the inflammatory response is essential for Src-induced transformation of mammary epithelial cells, and the cells' ability to form tumors is impeded when this pathway is blocked. Furthermore, Src activation promotes the expansion of the CSC population and CSCs have enhanced activity of the inflammatory pathway compared with non-CSCs. CSCs are therefore likely to exhibit increased dependence on the inflammatory feedback loop, and pharmacological interference with this pathway may limit their tumorigenic potential.

Bottom Line: 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.

View Article: PubMed Central - HTML - PubMed

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.

Show MeSH
Related in: MedlinePlus