p8 is a new target of gemcitabine in pancreatic cancer cells.
Gemcitabine is the only available chemotherapeutic treatment of pancreatic cancers. It is, however, moderately effective, showing a tumor response rate of only 12%. The aim of this work was to identify new pathways involved in the resistance of pancreatic cancer cells to gemcitabine, in the hope of developing new adjuvant strategies to enhance its therapeutic efficacy. Comparison of gene expression patterns of five human pancreatic cancer cell lines showing different degrees of resistance to gemcitabine revealed specific overexpression of several genes in the most resistant. One of them encoded the antiapoptotic p8 protein. We found that (a) knocking down p8 expression in gemcitabine-resistant cells promoted cell death and increased caspase-3 activity; (b) forced overexpression of p8 in gemcitabine-sensitive cells increased their resistance to gemcitabine-induced apoptosis; and (c) gemcitabine down-regulated p8 mRNA expression. These results suggest that, in pancreatic cancer cells, a large part of gemcitabine-induced apoptosis results from the inhibition of the constitutive antiapoptotic activity of p8. Hence, targeting the p8-associated pathway could be a new adjuvant therapy improving the response of patients with pancreatic cancer to gemcitabine treatment.
Giroux
Valentin
V
Institut National de la Sante et de la Recherche Medicale, Unité 624, Stress Cellulaire, Parc Scientifique et Technologique de Luminy, Marseille, France.
Malicet
Cédric
C
Barthet
Marc
M
Gironella
Meritxell
M
Archange
Cendrine
C
Dagorn
Jean-Charles
JC
Vasseur
Sophie
S
Iovanna
Juan L
JL
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051792:Basic Helix-Loop-Helix Proteins / Q000187:drug effects / Q000378:metabolism*; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005434:Flow Cytometry; D015870:Gene Expression; D006801:Humans; D009363:Neoplasm Proteins / Q000187:drug effects / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D051792:Basic Helix-Loop-Helix Proteins; D003841:Deoxycytidine; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D000093542:Gemcitabine; C491643:NUPR1 protein, human