title: Arsenic trioxide induces apoptosis in pancreatic cancer cells via changes in cell cycle, caspase activation, and GADD expression.
abstract: We have previously shown that arsenic trioxide blocks proliferation and induces apoptosis in human pancreatic cancer cells at low, non-toxic concentrations. The mechanisms of the apoptosis was investigated in MiaPaCa2 and PANC-1 cells that have been previously shown to be responsive to arsenic trioxide. The results show the caspase-3, caspase-7, and caspase-9 are all activated by arsenic trioxide, together with cleavage of the downstream caspase-3 target poly ADP ribose polymerase (PARP). Expression of the anti-apoptosis proteins, Bcl-2 and Mcl-1 expression decreased time-dependently while Bax expression increased. These findings indicate that the Bcl family of proteins, the mitochondrial pathway and activation of the caspase cascade are responsible for arsenic-induced apoptosis. Flow cytometric analysis revealed changes of cell cycle distribution from a G0/G1 phase arrest at 24 hours to G2/M phase arrest at 72 hours following arsenic treatment. The sub-G0/G1 cell population of apoptotic cells was increased at these times. Arsenic increased expression of the P21 protein and decreased levels of cyclin A, cyclin B1 and cyclin D1, but expression of CDK2, CDK4, CDK6, and cyclin E were not affected. Arsenic trioxide markedly enhanced the expression of GADD45 and GADD153 in a time-dependent manner. In summary, arsenic trioxide induced apoptosis in pancreatic cancer cells through activating the caspase cascade via the mitochondrial pathway, GADD expression and by modifying cell cycle progress and changes in several cycle-regulating proteins. This old drug may be valuable for treatment of pancreatic cancer.
authors.affiliation: Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Xinquan
authors.initials: X
authors.lastname: Li
authors.forename: Xianzhong
authors.initials: X
authors.lastname: Ding
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Adrian
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D015153:Blotting, Western; D022762:CCAAT-Enhancer-Binding Proteins; D053148:Caspase 3; D053179:Caspase 7; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000378:metabolism; D010087:Oxides / Q000494:pharmacology*; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013997:Time Factors; D051742:Transcription Factor CHOP; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D051028:bcl-2-Associated X Protein; D000097642:GADD45 Proteins
chemical_list: D000077237:Arsenic Trioxide; D001152:Arsenicals; D022762:CCAAT-Enhancer-Binding Proteins; D053148:Caspase 3; D053179:Caspase 7; D053453:Caspase 9; D020169:Caspases; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins; D047908:Intracellular Signaling Peptides and Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D010087:Oxides; D011065:Poly(ADP-ribose) Polymerases; D011506:Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051742:Transcription Factor CHOP; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D051028:bcl-2-Associated X Protein; D000097642:GADD45 Proteins; C494826:BAX protein, human; C493956:CDKN1A protein, human; C497249:DDIT3 protein, human; C505407:CASP3 protein, human; C505520:CASP7 protein, human; C506433:CASP9 protein, human