Drug resistance associated with loss of p53 involves extensive alterations in microtubule composition and dynamics

Br J Cancer. 2003 Jun 2;88(11):1793-9. doi: 10.1038/sj.bjc.6600960.

Abstract

In the present study, we compared the dynamics and composition of microtubules in cell lines derived from the human breast adenocarcinoma MCF-7 containing either the wild-type p53 (wt-p53; MN1) or a dominant-negative variant of p53 gene (mut-p53; MDD2). Mut-p53 cells were significantly resistant to the cytotoxicity of the microtubule-targeted drugs (vinca alkaloids and taxanes), as compared with wt-p53 cells. Studies by high-resolution time-lapse fluorescence microscopy in living cells indicated that the dynamics of microtubules of mut-p53 cells were altered in complex ways and were significantly increased as compared with microtubules in wt-p53 cells. The percentage of time microtubules spent in growing and shortening phases increased significantly, their catastrophe frequency increased, and their overall dynamicity increased by 33%. In contrast, their shortening rate and the mean length shortened decreased. Cells containing mut-p53 displayed increased polymerisation of tubulin, increased protein levels of the class IV beta-tubulin isotype, STOP and survivin, and reduced protein levels of class II beta-tubulin isotype, MAP4 and FHIT. We conclude that p53 protein may contribute to the regulation of microtubule composition and function, and that alterations in p53 function may generate complex microtubule-associated mechanisms of resistance to tubulin-binding agents.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acid Anhydride Hydrolases*
  • Adenocarcinoma / metabolism*
  • Adenocarcinoma / pathology
  • Animals
  • Antigens, Neoplasm / metabolism
  • Antineoplastic Agents / pharmacology*
  • Blotting, Western
  • Brain / metabolism
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Cattle
  • DNA Primers / chemistry
  • Drug Resistance, Neoplasm*
  • Genes, Tumor Suppressor
  • Humans
  • Inhibitor of Apoptosis Proteins
  • Luciferases / metabolism
  • Microtubule-Associated Proteins / metabolism
  • Microtubules / metabolism*
  • Mutation / genetics
  • Neoplasm Proteins / metabolism
  • Nerve Tissue Proteins / metabolism
  • Promoter Regions, Genetic
  • Reverse Transcriptase Polymerase Chain Reaction
  • Survivin
  • Transfection
  • Tubulin / metabolism
  • Tumor Cells, Cultured
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • Antigens, Neoplasm
  • Antineoplastic Agents
  • BIRC5 protein, human
  • DNA Primers
  • Inhibitor of Apoptosis Proteins
  • MAP4
  • MAP6 protein, human
  • Microtubule-Associated Proteins
  • Neoplasm Proteins
  • Nerve Tissue Proteins
  • Survivin
  • Tubulin
  • Tumor Suppressor Protein p53
  • fragile histidine triad protein
  • Luciferases
  • Acid Anhydride Hydrolases