Evidence for activation of mutated p53 by apigenin in human pancreatic cancer.
Pancreatic cancer is an exceedingly lethal disease with a five-year survival that ranks among the lowest of gastrointestinal malignancies. Part of its lethality is attributable to a generally poor response to existing chemotherapeutic regimens. New therapeutic approaches are urgently needed. We aimed to elucidate the anti-neoplastic mechanisms of apigenin-an abundant, naturally-occurring plant flavonoid-with a particular focus on p53 function. Pancreatic cancer cells (BxPC-3, MiaPaCa-2) experienced dose and time-dependent growth inhibition and increased apoptosis with apigenin treatment. p53 post-translational modification, nuclear translocation, DNA binding, and upregulation of p21 and PUMA were all enhanced by apigenin treatment despite mutated p53 in both cell lines. Transcription-dependent p53 activity was reversed by pifithrin-α, a specific DNA binding inhibitor of p53, but not growth inhibition or apoptosis suggesting transcription-independent p53 activity. This was supported by immunoprecipitation assays which demonstrated disassociation of p53/BclXL and PUMA/BclXL and formation of complexes with Bak followed by cytochrome c release. Treated animals grew smaller tumors with increased cellular apoptosis than those fed control diet. These results suggest that despite deactivating mutation, p53 retains some of its function which is augmented following treatment with apigenin. Cell cycle arrest and apoptosis induction may be mediated by transcription-independent p53 function via interactions with BclXL and PUMA. Further study of flavonoids as chemotherapeutics is warranted.
Department of Surgery, David Geffen School of Medicine at UCLA, 72-107 CHS, 10833 LeConte Ave, Los Angeles, CA 90095, USA.
Jonathan C
JC
King
Qing-Yi
QY
Lu
Gang
G
Li
Aune
A
Moro
Hiroki
H
Takahashi
Monica
M
Chen
Vay Liang W
VL
Go
Howard A
HA
Reber
Guido
G
Eibl
O Joe
OJ
Hines
D000818:Animals; D047310:Apigenin / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D052160:Benzothiazoles / Q000378:metabolism; D045744:Cell Line, Tumor; D019587:Dietary Supplements; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D009374:Neoplasms, Experimental / Q000378:metabolism / Q000628:therapy; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D014050:Toluene / Q000031:analogs & derivatives / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; C494811:BCL2L1 protein, human; D052160:Benzothiazoles; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D051020:bcl-X Protein; D014050:Toluene; D047310:Apigenin; C121565:pifithrin