RNA interference targeting focal adhesion kinase enhances pancreatic adenocarcinoma gemcitabine chemosensitivity.
Focal adhesion kinase (FAK) is an important regulator of cellular signaling, migration, apoptosis, and cell cycle progression. We tested the hypothesis that FAK is a determinant of gemcitabine chemoresistance in pancreatic adenocarcinoma cells and examined the effect of inhibiting FAK expression on gemcitabine-induced cytotoxicity in vitro and in vivo. FAK expression was quantified by Western and Northern blots. Expression of FAK was suppressed using small interfering RNA (siRNA). Gemcitabine-induced cytotoxicity was quantified and apoptosis was characterized. Akt activity was determined by in vitro kinase assay. We assessed the therapeutic applicability of FAK siRNA in a nude mouse orthotopic xenograft model. While not affecting cellular proliferation or apoptosis in the absence of gemcitabine, FAK siRNA potentiated gemcitabine-induced cytotoxicity in vitro and in vivo. FAK siRNA treatment suppressed Akt activity, which may contribute to its chemosensitizing effect.
Duxbury
Mark S
MS
Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Ito
Hiromichi
H
Benoit
Eric
E
Zinner
Michael J
MJ
Ashley
Stanley W
SW
Whang
Edward E
EE
D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D015152:Blotting, Northern; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010179:Pancreas / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D012313:RNA / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D014162:Transfection; D000093542:Gemcitabine
D004791:Enzyme Inhibitors; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D003841:Deoxycytidine; D012313:RNA; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human; C496051:Ptk2 protein, mouse; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020169:Caspases; D000093542:Gemcitabine