TY  - JOUR
A1  - Moench, Romana
A1  - Grimmig, Tanja
A1  - Kannen, Vinicius
A1  - Tripathi, Sudipta
A1  - Faber, Marc
A1  - Moll, Eva-Maria
A1  - Chandraker, Anil
A1  - Lissner, Reinhard
A1  - Germer, Christoph-Thomas
A1  - Waaga-Gasser, Ana Maria
A1  - Gasser, Martin
T1  - Exclusive inhibition of PI3K/Akt/mTOR signaling is not sufficient to prevent PDGF-mediated effects on glycolysis and proliferation in colorectal cancer
JF  - Oncotarget
N2  - 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.
KW  - PDGF
KW  - colorectal cancer
KW  - MAPK pathway
KW  - glucose metabolism
KW  - PI3K/Akt/mTOR
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-176910
VL  - 7
IS  - 42
ER  - 
TY  - JOUR
A1  - Van Steenbergen, Anne
A1  - Balteau, Magali
A1  - Ginion, Audrey
A1  - Ferté, Laura
A1  - Battault, Sylvain
A1  - de Meester de Ravenstein, Christophe
A1  - Balligand, Jean-Luc
A1  - Daskalopoulos, Evangelos-Panagiotis
A1  - Gilon, Patrick
A1  - Despa, Florin
A1  - Despa, Sanda
A1  - Vanoverschelde, Jean-Louis
A1  - Horman, Sandrine
A1  - Koepsell, Hermann
A1  - Berry, Gerard
A1  - Hue, Louis
A1  - Bertrand, Luc
A1  - Beauloye, Christophe
T1  - Sodium-myoinositol cotransporter-1, SMIT1, mediates the production of reactive oxygen species induced by hyperglycemia in the heart
JF  - Scientific Reports
N2  - Hyperglycemia (HG) stimulates the production of reactive oxygen species in the heart through activation of NADPH oxidase 2 (NOX2). This production is independent of glucose metabolism but requires sodium/glucose cotransporters (SGLT). Seven SGLT isoforms (SGLT1 to 6 and sodium-myoinositol cotransporter-1, SMIT1) are known, although their expression and function in the heart remain elusive. We investigated these 7 isoforms and found that only SGLT1 and SMIT1 were expressed in mouse, rat and human hearts. In cardiomyocytes, galactose (transported through SGLT1) did not activate NOX2. Accordingly, SGLT1 deficiency did not prevent HG-induced NOX2 activation, ruling it out in the cellular response to HG. In contrast, myo-inositol (transported through SMIT1) reproduced the toxic effects of HG. SMIT1 overexpression exacerbated glucotoxicity and sensitized cardiomyocytes to HG, whereas its deletion prevented HG-induced NOX2 activation. In conclusion, our results show that heart SMIT1 senses HG and triggers NOX2 activation. This could participate in the redox signaling in hyperglycemic heart and contribute to the pathophysiology of diabetic cardiomyopathy.
KW  - hyperglycemia
KW  - Sodium-myoinositol cotransporter-1 (SMIT1)
KW  - glucose metabolism
KW  - heart
KW  - NADPH oxidase 2 (NOX2)
KW  - sodium/glucose cotransporters (SGLT)
KW  - cardiomyocytes
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-180891
VL  - 7
ER  -