Proteolysis of microtubule associated protein 2 and sensitivity of pancreatic tumours to docetaxel.
We have studied the state of microtubule associated protein 2 (MAP2) in the pancreatic ductal adenocarcinomas P03 and P02 (sensitive and refractory to docetaxel respectively) since they express the corresponding mRNA and MAP2-related peptides. Immunohistochemical localization showed that in tumour P03 the MAP2-related peptides are highly expressed and confined to the epithelial malignant cells while in P02 the Intensity of the immunostaining is lower. However, anti alpha-tubulin staining followed a similar pattern suggesting that the net amount of macromolecular structures in the sensitive tumour is higher than in the refractory one. This may explain its higher sensitivity to docetaxel, because tubulin assembled into microtubules is the target of the drug. We found that protein extracts from both tumours differed in their proteolytic activity on rat brain MAP2. Since the proteolysis pattern obtained was similar to the one produced by Cathepsin D, we studied the effect of MAP2 proteolysed by this enzyme on microtubule formation in vitro. Proteolysis was found to increase the tendency of tubulin to assemble into macromolecular structures (microtubules and aggregates) in the presence of docetaxel. This suggests that in vivo proteolysis of MAP2 might increase microtubule alterations and potentiate the antitumour effect of docetaxel.
Veitia
R
R
Unité d'Immunogénétique Humaine, Institut Pasteur, Paris, France.
David
S
S
Barbier
P
P
Vantard
M
M
Gounon
P
P
Bissery
M C
MC
Fellous
A
A
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D018270:Carcinoma, Ductal, Breast / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism*; D002402:Cathepsin D / Q000378:metabolism / Q000494:pharmacology; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D007150:Immunohistochemistry; D007700:Kinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008854:Microscopy, Electron; D008869:Microtubule-Associated Proteins / Q000276:immunology / Q000378:metabolism*; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D008969:Molecular Sequence Data; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000494:pharmacology*; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism*; D010447:Peptide Hydrolases / Q000378:metabolism; D010455:Peptides / Q000276:immunology / Q000378:metabolism; D051381:Rats; D043823:Taxoids; D014404:Tubulin / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D000972:Antineoplastic Agents, Phytogenic; D008869:Microtubule-Associated Proteins; D010455:Peptides; D043823:Taxoids; D014404:Tubulin; D000077143:Docetaxel; D010447:Peptide Hydrolases; D002402:Cathepsin D; D017239:Paclitaxel