ZM336372 induces apoptosis associated with phosphorylation of GSK-3beta in pancreatic adenocarcinoma cell lines.
BACKGROUND
ZM336372 is small molecule tyrosine kinase modulator. It has been shown to inhibit glycogen synthase kinase-3beta (GSK-3beta) through phosphorylation of GSK-3beta at Ser 9. GSK-3beta has previously been shown to mediate cell survival in pancreatic cancer cells. Here we determine the effects of ZM336372 on GSK-3beta phosphorylation, apoptosis, and growth in pancreatic adenocarcinoma cell lines.


METHODS
Panc-1 and MiaPaCa-2 cells were treated with ZM336372 or lithium chloride (LiCl) and compared with solvent control. The effects on proliferation for each cell line were determined using the MTT assay. Western blot analysis was performed to examine the effects of treatment on the phosphorylation of GSK-3beta. In addition, western blot was utilized to examine the cleavage of poly (ADP-ribose) polymerase (PARP), a marker of apoptosis.


RESULTS
A dose-dependent increase in phosphorylation of GSK-3beta was observed after treatment with both ZM336372 and LiCl. Growth inhibition due to treatment with ZM336372 and LiCl also occurred in a dose-dependent fashion. An increase in cleaved PARP was demonstrated after treatment with both agents, as was seen previously with GSK-3beta inhibition in pancreatic adenocarcinoma cells.


CONCLUSIONS
This is the first description of growth inhibition and apoptosis in pancreatic cancer cells related to GSK-3beta inhibition through treatment with ZM336372.
Deming
Dustin
D
Department of Medicine, University of Wisconsin, Madison, Wisconsin 53792, USA.
Geiger
Peter
P
Chen
Herbert
H
Kunnimalaiyaan
Muthusamy
M
Holen
Kyle
K
D000230:Adenocarcinoma / Q000188:drug therapy*; D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D018021:Lithium Chloride / Q000494:pharmacology; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D010766:Phosphorylation / Q000187:drug effects; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism
D001549:Benzamides; C121825:N-(5-(3-dimethylaminobenzamido)-2-methylphenyl)-4-hydroxybenzamide; D011065:Poly(ADP-ribose) Polymerases; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D018021:Lithium Chloride