Metformin, an antidiabetic agent reduces growth of cutaneous squamous cell carcinoma by targeting mTOR signaling pathway

Photochem Photobiol. Sep-Oct 2012;88(5):1149-56. doi: 10.1111/j.1751-1097.2012.01165.x. Epub 2012 Jun 1.

Abstract

The biguanide metformin is widely used for the treatment of Type-II diabetes. Its antiproliferative and pro-apoptotic effects in various tumor cells suggest its potential candidacy for cancer chemoprevention. Herein, we report that metformin significantly inhibited human epidermoid A431 tumor xenograft growth in nu/nu mice, which was associated with a significant reduction in proliferative biomarkers PCNA and cyclins D1/B1. This tumor growth reduction was accompanied by the enhanced apoptotic cell death and an increase in Bax:Bcl2 ratio. The mechanism by which metformin manifests antitumor effects appears to be dependent on the inhibition of nuclear factor kappa B (NFkB) and mTOR signaling pathways. Decreased phosphorylation of NFkB inhibitory protein IKBα together with reduced enhancement of NFkB transcriptional target proteins, iNOS/COX-2 were observed. In addition, a decrease in the activation of ERK/p38-driven MAP kinase signaling was seen. Similarly, AKT signaling activation as assessed by the diminished phosphorylation at Ser473 with a concomitant decrease in mTOR signaling pathway was also noted as phosphorylation of mTOR regulatory proteins p70S6K and 4E-BP-1 was significantly reduced. Consistently, decreased phosphorylation of GSK3β, which is carried out by AKT kinases was also observed. These results suggest that metformin blocks SCC growth by dampening NFkB and mTOR signaling pathways.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism
  • Carcinoma, Squamous Cell / drug therapy*
  • Carcinoma, Squamous Cell / metabolism
  • Carcinoma, Squamous Cell / pathology
  • Cyclin B1 / genetics
  • Cyclin B1 / metabolism
  • Cyclin D1 / genetics
  • Cyclin D1 / metabolism
  • Cyclooxygenase 2 / genetics
  • Cyclooxygenase 2 / metabolism
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Hypoglycemic Agents / pharmacology*
  • Metformin / pharmacology*
  • Mice
  • Mice, Nude
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Nitric Oxide Synthase Type II / genetics
  • Nitric Oxide Synthase Type II / metabolism
  • Proliferating Cell Nuclear Antigen / genetics
  • Proliferating Cell Nuclear Antigen / metabolism
  • Signal Transduction / drug effects
  • Skin / drug effects*
  • Skin / pathology
  • Skin Neoplasms / drug therapy*
  • Skin Neoplasms / metabolism
  • Skin Neoplasms / pathology
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism
  • bcl-2-Associated X Protein / genetics
  • bcl-2-Associated X Protein / metabolism
  • bcl-Associated Death Protein / genetics
  • bcl-Associated Death Protein / metabolism

Substances

  • Antineoplastic Agents
  • Biomarkers, Tumor
  • Cyclin B1
  • Hypoglycemic Agents
  • NF-kappa B
  • Proliferating Cell Nuclear Antigen
  • bcl-2-Associated X Protein
  • bcl-Associated Death Protein
  • Cyclin D1
  • Metformin
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse
  • Ptgs2 protein, mouse
  • Cyclooxygenase 2
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse