Exclusive inhibition of PI3K/Akt/mTOR signaling is not sufficient to prevent PDGF-mediated effects on glycolysis and proliferation in colorectal cancer.
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.
Department of Surgery I, Molecular Oncology and Immunology, University of Wuerzburg, Wuerzburg, Germany.
Romana
R
Moench
Department of Surgery I, Molecular Oncology and Immunology, University of Wuerzburg, Wuerzburg, Germany.
Tanja
T
Grimmig
Ribeirao Preto Pharmaceutical Sciences School, Department of Toxicology, Bromatology, and Clinical Analysis, University of Sao Paulo, Sao Paulo, Brazil.
Vinicius
V
Kannen
Brigham and Women's Hospital, Transplant Research Center, Harvard Medical School, Boston, MA, USA.
Sudipta
S
Tripathi
Department of Surgery I, Molecular Oncology and Immunology, University of Wuerzburg, Wuerzburg, Germany.
Marc
M
Faber
Department of Surgery I, Molecular Oncology and Immunology, University of Wuerzburg, Wuerzburg, Germany.
Eva-Maria
EM
Moll
Brigham and Women's Hospital, Transplant Research Center, Harvard Medical School, Boston, MA, USA.
Anil
A
Chandraker
Department of Surgery I, Molecular Oncology and Immunology, University of Wuerzburg, Wuerzburg, Germany.
Reinhard
R
Lissner
Department of Surgery I, University of Wuerzburg, Wuerzburg, Germany.
Christoph-Thomas
CT
Germer
Department of Surgery I, Molecular Oncology and Immunology, University of Wuerzburg, Wuerzburg, Germany.|Brigham and Women's Hospital, Transplant Research Center, Harvard Medical School, Boston, MA, USA.
Ana Maria
AM
Waaga-Gasser
Department of Surgery I, University of Wuerzburg, Wuerzburg, Germany.
Martin
M
Gasser
D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology; D006019:Glycolysis / Q000187:drug effects*; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000494:pharmacology
D019869:Phosphatidylinositol 3-Kinases; D010982:Platelet-Derived Growth Factor; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D042461:Vascular Endothelial Growth Factor A; C546842:MTOR protein, human
MAPK pathway; PDGF; PI3K/Akt/mTOR; colorectal cancer; glucose metabolism