Inhibition of pancreatic cancer cell growth and induction of apoptosis with novel therapies directed against protein kinase A.
BACKGROUND
Pancreatic cancer is the most lethal abdominal malignancy. Expression of the RIalpha subunit of protein kinase A (PKA) has been associated with neoplastic transformation and mitogenic signaling. The effect of PKA inhibition on pancreatic cancer cell growth and apoptosis is unknown. In pancreatic cancer cells, we sought to determine (1) whether inhibition of PKA can inhibit growth or induce apoptosis, and (2) whether growth can be inhibited by silencing of RIalpha expression.


METHODS
Human pancreatic cancer cells (PANC-1, MIA PaCa-2, and SUIT-2) were treated with inhibitors of PKA (H89 or PKI) and cell growth, kinase activity, and induction of apoptosis measured. Small inhibitory RNA (siRNA) directed against the RIalpha subunit was synthesized and transfected into PANC-1 cells.


RESULTS
H89 decreased PKA activity and inhibited pancreatic cancer cell growth. Apoptosis was also induced by H89 in PANC-1 and MIA PaCa-2 cells. PANC-1 cells express high levels of the RIalpha subunit; transfection of siRNA decreased RIalpha protein expression and inhibited growth.


CONCLUSIONS
Inhibition of PKA in pancreatic cancer cells induces growth arrest and apoptosis; similar effects are noted in cells with siRNA used to block RIalpha expression. Inhibition of PKA may represent a novel therapeutic strategy for the adjuvant treatment of pancreatic cancer.
Farrow
Buckminster
B
Department of Surgery, the University of Texas Medical Branch, Galveston, TX, USA.
Rychahou
Piotr
P
Murillo
Carlos
C
O'connor
Kathleen L
KL
Iwamura
Takeshi
T
Evers
B Mark
BM
D017209:Apoptosis; D001483:Base Sequence / Q000235:genetics; D002352:Carrier Proteins / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology*; D008969:Molecular Sequence Data; D010190:Pancreatic Neoplasms / Q000473:pathology* / Q000503:physiopathology*; D010446:Peptide Fragments / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology*; D013449:Sulfonamides; D014407:Tumor Cells, Cultured; D051028:bcl-2-Associated X Protein
D002352:Carrier Proteins; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; D004791:Enzyme Inhibitors; D007546:Isoquinolines; C517834:PRKAR1A protein, human; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D013449:Sulfonamides; D051028:bcl-2-Associated X Protein; C477818:myristoylated protein kinase A inhibitor amide 14-22; D017868:Cyclic AMP-Dependent Protein Kinases; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide