Combined targeting of the VEGFr/EGFr and the mammalian target of rapamycin (mTOR) signaling pathway delays cell cycle progression and alters adhesion behavior of prostate carcinoma cells.
The impact of the mTOR inhibitor RAD001 combined with the EGFr/VEGFr tyrosine kinase inhibitor AEE788 on prostate tumor cell growth, adhesion and migration was analyzed in vitro. The RAD001-AEE788 combination profoundly reduced tumor-endothelium and tumor-matrix contacts, suppressing cell growth and cell cycle progression. The underlying molecular mode of action depended on the cell phenotype, since cell cycle proteins, integrin subtype expression and integrin dependent signaling were altered in a different manner in PC-3 and DU-145 versus LNCaP prostate cancer cells. Simultaneous targeting of mTOR and VEGFr/EGFr related pathways may offer a novel therapeutic strategy for prostate cancer treatment.
Department of Urology, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany.
Steffen
S
Wedel
Lukasz
L
Hudak
Jens-Michael
JM
Seibel
Eva
E
Juengel
Igor
I
Tsaur
Axel
A
Haferkamp
Roman A
RA
Blaheta
D002448:Cell Adhesion / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000502:physiology; D000068338:Everolimus; D006801:Humans; D008297:Male; D009361:Neoplasm Invasiveness; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011687:Purines / Q000494:pharmacology; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects*; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology
D047428:Protein Kinase Inhibitors; D011687:Purines; D000068338:Everolimus; C546842:MTOR protein, human; D066246:ErbB Receptors; D040262:Receptors, Vascular Endothelial Growth Factor; D058570:TOR Serine-Threonine Kinases; C489254:AEE 788; D020123:Sirolimus