Effects of the proteasome inhibitor bortezomib on gene expression profiles of pancreatic cancer cells.
BACKGROUND
Pancreatic cancer remains a highly chemoresistant malignancy. Gemcitabine is a widely used clinical chemotherapeutic agent against locally advanced and metastatic pancreatic cancer. Proteasome inhibitor bortezomib has been shown to result in enhanced cytotoxicity and apoptosis when used alone or in combination with gemcitabine in pancreatic cancer cell lines.


METHODS
To determine the effect of bortezomib on gene expression profile of pancreatic adenocarcinoma cells with different sensitivity to gemcitabine, we used Affymetrix HG U133A 2.0 GeneChip (Santa Clara, CA) and measured changes induced by bortezomib in pancreatic cancer cell lines with high (BxPC-3) and low (PANC-1) sensitivity to gemcitabine, at time points 24 h. Selected genes were subsequently validated by quantitative real-time polymerase chain reaction.


RESULTS
Forty-four common genes in both PANC-1 and BxPC-3 cells were identified as up-regulated (>3-fold) induced by bortezomib analyzed by microarray, which are associated with multiple cytotoxic and cytoprotective effects. Bcl-2 was repressed by bortezomib in both PANC-1 and BxPC-3 cells, while no changes induced in either cell by bortezomib were disclosed in all five members of nuclear factor-kappa B family. Other interesting genes related to apoptosis or drug metabolism, such as TP53 and ABCB1 (mdr1), were not found differentially expressed in common.


CONCLUSIONS
Bortezomib exhibits antitumor effects toward pancreatic cancer in vitro and in vivo. Genes with divergent apoptotic effects are induced by bortezomib, which may become promising targets for pancreatic cancer treatment.
Tang
Zhi-Yu
ZY
Department of Surgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
Wu
Yu-Lian
YL
Gao
Shun-Liang
SL
Shen
Hong-Wei
HW
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011480:Protease Inhibitors / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D000093542:Gemcitabine
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000964:Antimetabolites, Antineoplastic; D001897:Boronic Acids; D016328:NF-kappa B; D011480:Protease Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D011719:Pyrazines; D016159:Tumor Suppressor Protein p53; D003841:Deoxycytidine; D000069286:Bortezomib; D000093542:Gemcitabine