Apigenin inhibits NNK-induced focal adhesion kinase activation in pancreatic cancer cells.
OBJECTIVE
Tobacco-derived carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) activates β-adrenergic receptor (β-AR) signaling through Src/focal adhesion kinases (FAKs)/mitogen-activated protein kinase to modulate proliferation, migration, and survival. Apigenin (4', 5, 7-trihydroxyflavone) is reported to attenuate proliferation and migration of cancer cells. This study was designed to determine the effects of apigenin on NNK-induced procarcinogenesis using human pancreatic cancer cells BxPC-3 and MIA PaCa-2, which express β-AR.


METHODS
Proliferation and migration were assessed by standard 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and scratch assays. β-AR, FAK/mitogen-activated protein kinase and extracellular signal-regulated kinase (ERK) expression and activation were assessed by Western blotting and real-time polymerase chain reaction.


RESULTS
4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone caused a dose- and time-dependent increase in BxPC-3 and MIA PaCa-2 cell proliferation that was inhibited by propranolol or apigenin. 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone also stimulated a time-dependent increase in FAK and ERK activation that was suppressed by propranolol or apigenin. 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone-enhanced gap closure at 24 hours was prevented by either propranolol or apigenin.


CONCLUSIONS
Apigenin suppressed the effects of NNK on pancreatic cancer cell proliferation and migration that are mediated through the β-AR and its downstream signals FAK and ERK activation. These findings suggest a therapeutic role for this natural phytochemical in attenuating the procarcinogenic effects of NNK on pancreatic cancer proliferation and migration.
Department of Medicine, Veterans Affair Greater Los Angeles Healthcare System, Los Angeles, CA 90073, USA. zero@ucla.edu
Hung
H
Pham
Monica
M
Chen
Hiroki
H
Takahashi
Jonathan
J
King
Howard A
HA
Reber
Oscar Joe
OJ
Hines
Stephen
S
Pandol
Guido
G
Eibl
D000970:Antineoplastic Agents / Q000494:pharmacology*; D047310:Apigenin / Q000494:pharmacology*; D002273:Carcinogens / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D009602:Nitrosamines / Q000494:pharmacology*; D010190:Pancreatic Neoplasms / Q000201:enzymology*; D011433:Propranolol / Q000494:pharmacology; D011943:Receptors, Adrenergic, beta / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects
D000970:Antineoplastic Agents; D002273:Carcinogens; D009602:Nitrosamines; D011943:Receptors, Adrenergic, beta; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D047310:Apigenin; D011433:Propranolol; D051416:Focal Adhesion Protein-Tyrosine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases