Tau expression in model adenocarcinomas correlates with docetaxel sensitivity in tumour-bearing mice

Abstract

Docetaxel is a new taxoid with clinical activity in breast and lung cancer. Using docetaxel-sensitive and -refractory mammary and pancreatic murine tumours, as well as human-derived neoplasms, we investigated if a determinant of docetaxel sensitivity could be found at the level of its mechanism of action. Because microtubules represent the cellular targets of the drug, we studied their heterogeneity in the tumour models to try to explain the differences in drug sensitivity. Reverse transcription-polymerase chain reaction (RT-PCR) analysis of the expression of microtubular components showed that levels of Mbeta4-tubulin and Tau mRNAs were higher in the murine sensitive neoplasms than in the refractory ones. It was also found that Tau protein levels differed markedly among the tumours. In the human-derived sensitive neoplasm, beta-tubulins and some Tau isoforms were found to be more abundant than in the resistant one. Western blot analysis of MAP2 revealed the presence of several immunoreactive species. Some of these polypeptides were also found in higher amounts in the docetaxel-sensitive tumours. The possible meaning of these correlations is discussed in connection with the regulation of microtubule dynamics. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6

Proteolysis of microtubule associated protein 2 and sensitivity of pancreatic tumours to docetaxel

“…Docetaxel was highly active in vivo against advanced stage pancreatic ductal adenocarcinoma P03 and inactive against early stage P02 (Bissery et al, 1991;Veitia et al, 1998). We showed that the sensitive tumour P03 expresses a higher level of Tau proteins when compared to the docetaxel refractory neoplasm P02 (Veitia et al, 1998). This higher quantity of Tau may increase the sensitivity to the drug since both Tau and docetaxel stabilize microtubules.…”

“…Anti-MAP2 152 is a monoclonal produced in our laboratory (Kalil et al, 1988;Veitia et al, 1998 Summary 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.…”

“…Western blots were carried out as described by Veitia et al (1998) using the following antibodies: anti α-tubulin (Sigma), anti MAP2-152, polyclonal anti-Cathepsin D (DAKO) and the two polyclonals anti-TBD PromA and Prom M.…”

“…This higher quantity of Tau may increase the sensitivity to the drug since both Tau and docetaxel stabilize microtubules. In this report we concentrate on MAP2 since we have shown that tumours P02 and P03 express the corresponding mRNA and that MAP2-related peptides are recognized by antibodies directed against the brain MAP2 protein (Veitia et al, 1998). In addition, it has been shown that proteolysis of MAP2 alters its interaction with tubulin and promotes tubulin aggregation into anomalous structures in the presence of vinblastine (Fellous et al, 1994).…”

Identification of a mouse cytoskeleton‐associated protein, CKAP2, with microtubule‐stabilizing properties

“…[35][36][37][38] Expression of tau was observed in tumors including astrocytomas, oligodendrogliomas, chondrosarcomas and gastrointestinal stromal tumors, [39][40][41] and tau phosphorylation is associated with anti-cancer drug sensitivity and drug-induced apoptosis. [42][43][44][45] We and other investigators found that expression of the CKAP2 gene is also upregulated in some human tumors. Because some anti-cancer drugs target microtubule dynamics, the status of MAPs in cells might play a crucial role in determining the drug sensitivity of cancer cells.…”