Oncotarget

Research Papers:

Metformin increases antitumor activity of MEK inhibitors through GLI1 downregulation in LKB1 positive human NSCLC cancer cells

Carminia Maria Della Corte, Vincenza Ciaramella, Concetta Di Mauro, Maria Domenica Castellone, Federica Papaccio, Morena Fasano, Ferdinando Carlo Sasso, Erika Martinelli, Teresa Troiani, Ferdinando De Vita, Michele Orditura, Roberto Bianco, Fortunato Ciardiello and Floriana Morgillo _

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Oncotarget. 2016; 7:4265-4278. https://doi.org/10.18632/oncotarget.6559

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Abstract

Carminia Maria Della Corte1, Vincenza Ciaramella1, Concetta Di Mauro2, Maria Domenica Castellone3, Federica Papaccio1, Morena Fasano1, Ferdinando Carlo Sasso4, Erika Martinelli1, Teresa Troiani1, Ferdinando De Vita1, Michele Orditura1, Roberto Bianco2, Fortunato Ciardiello1, Floriana Morgillo1

1Oncologia Medica, Dipartimento Medico-Chirurgico di Internistica Clinica e Sperimentale “F. Magrassi e A. Lanzara”, Seconda Università degli Studi di Napoli, Naples, Italy

2Oncologia Medica, Dipartimento di Medicina Clinica e Chirurgia, Università degli studi di Napoli “Federico II”, Naples, Italy

3Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Istituto di Endocrinologia ed Oncologia Sperimentale “G. Salvatore” (IEOS), University of Naples “Federico II”, Naples, Italy

4Medicina Interna, Dipartimento Medico-Chirurgico di Internistica Clinica e Sperimentale “F. Magrassi e A. Lanzara”, Seconda Università degli Studi di Napoli, Naples, Italy

Correspondence to:

Floriana Morgillo, e-mail: florianamorgillo@yahoo.com

Keywords: metformin, MEK, selumetinib, pimasertib, NSCLC

Received: August 13, 2015     Accepted: November 25, 2015     Published: December 11, 2015

ABSTRACT

Purpose: Metformin, widely used as antidiabetic drug, showed antitumoral effects expecially in combination with chemotherapy. Our group recently has demonstrated that metformin and gefitinib are synergistic in LKB1-wild-type NSCLC cells. In these models, metformin as single agent induced an activation and phosphorylation of mitogen-activated-protein-kinase (MAPK) through an increased C-RAF/B-RAF heterodimerization.

Experimental design: Since single agent metformin enhances proliferating signals through the RAS/RAF/MAPK pathway, and several MEK inhibitors (MEK-I) demonstrated clinical efficacy in combination with other agents in NSCLC, we tested the effects of metformin plus MEK-I (selumetinib or pimasertib) on proliferation, invasiveness, migration abilities in vitro and in vivo in LKB1 positive NSCLC models harboring KRAS wild type and mutated gene.

Results: The combination of metformin with MEK-I showed a strong anti-proliferative and proapoptotic effect in Calu-3, H1299, H358 and H1975 human NSCLC cell lines, independently from the KRAS mutational status. The combination reduced the metastatic behaviour of NSCLC cells, via a downregulation of GLI1 trascritional activity, thus affecting the transition from an epithelial to a mesenchymal phenotype. Metformin and MEK-Is combinations also decreased the production and activity of MMP-2 and MMP-9 by reducing the NF-jB (p65) binding to MMP-2 and MMP-9 promoters.

Conclusions: Metformin potentiates the antitumor activity of MEK-Is in human LKB1-wild-type NSCLC cell lines, independently from the KRAS mutational status, through GLI1 downregulation and by reducing the NF-jB (p65)-mediated transcription of MMP-2 and MMP-9.


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