Oncotarget

Research Papers:

Exclusive inhibition of PI3K/Akt/mTOR signaling is not sufficient to prevent PDGF-mediated effects on glycolysis and proliferation in colorectal cancer

Romana Moench, Tanja Grimmig, Vinicius Kannen, Sudipta Tripathi, Marc Faber, Eva-Maria Moll, Anil Chandraker, Reinhard Lissner, Christoph-Thomas Germer, Ana Maria Waaga-Gasser, _ Martin Gasser

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Oncotarget. 2016; 7:68749-68767. https://doi.org/10.18632/oncotarget.11899

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Abstract

Romana Moench1, Tanja Grimmig1, Vinicius Kannen2, Sudipta Tripathi3, Marc Faber1, Eva-Maria Moll1,, Anil Chandraker3, Reinhard Lissner1, Christoph-Thomas Germer4, Ana Maria Waaga-Gasser1,3,*, Martin Gasser4,*

1Department of Surgery I, Molecular Oncology and Immunology, University of Wuerzburg, Wuerzburg, Germany

2Ribeirao Preto Pharmaceutical Sciences School, Department of Toxicology, Bromatology, and Clinical Analysis, University of Sao Paulo, Sao Paulo, Brazil

3Brigham and Women’s Hospital, Transplant Research Center, Harvard Medical School, Boston, MA, USA

4Department of Surgery I, University of Wuerzburg, Wuerzburg, Germany

Post mortem

*These authors have contributed equally to this work and shared senior authorship

Correspondence to:

Ana Maria Waaga-Gasser, email: waaga_a@ukw.de

Keywords: PDGF, colorectal cancer, PI3K/Akt/mTOR, MAPK pathway, glucose metabolism

Received: January 21, 2016     Accepted: August 08, 2016     Published: September 08, 2016

ABSTRACT

Platelet-derived growth factor (PDGF) and signaling via its receptors plays a crucial role in tumor cell proliferation and thus may represent an attractive target besides VEGF/EGFR-based antibody therapies. In this study we analyzed the influence of PDGF in colorectal cancer. PDGF was expressed intensively in early and even more intensively in late stage primary CRCs. Like VEGF, PDGF enhanced human colon cancer proliferation, and increased oxidative glycolytic activity, and activated HIF1α and c-Myc in vitro. PDGF activated the PI3K/Akt/mTOR pathway while leaving MAPK signaling untouched. Further dissection showed that inhibition of Akt strongly impeded cancer cell growth while inhibition of PI3K did not. MAPK analysis suggested an inhibitory crosstalk between both pathways, thus explaining the different effects of the Akt and PI3K inhibitors on cancer cell proliferation. PDGF stimulates colon cancer cell proliferation, and prevents inhibitor induced apoptosis, resulting in tumor growth. Therefore inhibition of PDGF signaling seems to be a promising target in colorectal cancer therapy. However, due to the multifaceted nature of the intracellular PDGF signaling, careful intervention strategies are needed when looking into specific signaling pathways like PI3K/Akt/mTOR and MAPK.


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