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Yeast As a Chassis for Developing Functional Assays to Study Human P53
14:57

Yeast As a Chassis for Developing Functional Assays to Study Human P53

Published on: August 4, 2019

Inactivation of wild-type p53 by a dominant negative mutant renders MCF-7 cells resistant to tubulin-binding agent

C M Galmarini1, N Falette, E Tabone

  • 1INSERM 453, Laboratoire de Cytologie Analytique, Faculté de Médecine Rockefeller 8, Avenue Rockefeller, 69373, Lyon CEDEX 08, France.

British Journal of Cancer
|September 15, 2001
PubMed

Insights

The p53 protein status significantly impacts cancer cell sensitivity to tubulin-binding agents (TBAs). Wild-type p53 (wt-p53) enhances TBA cytotoxicity and apoptosis, while mutated p53 (mut-p53) confers resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • The role of p53 in cancer cell response to chemotherapy is complex.
  • Tubulin-binding agents (TBAs) are a class of chemotherapy drugs targeting cancer cell division.

Purpose of the Study:

  • To investigate how the p53 protein status influences the cytotoxicity of TBAs in cancer cells.
  • To compare drug sensitivity, cell cycle effects, and apoptosis induction in cancer cell lines with wild-type versus mutated p53.

Main Methods:

  • Utilized two MCF-7 derived mammary adenocarcinoma cell lines: MN-1 (wild-type p53) and MDD2 (mutated p53).
  • Assessed drug sensitivity, cell cycle distribution (G2/M arrest), apoptosis (annexin V, PARP cleavage), p53 accumulation, and downstream protein induction (p21/WAF1, cyclin G1) after TBA exposure.
  • Measured mitochondrial membrane potential and Raf-1 kinase activity.
  • Investigated the effect of flavopiridol in combination with TBAs.

Main Results:

  • The MDD2 (mut-p53) cell line exhibited significantly greater resistance to vinblastine and paclitaxel compared to the MN-1 (wt-p53) cell line.
  • MN-1 cells showed wt-p53 accumulation and induction of p21/WAF1 and cyclin G1 upon TBA exposure, unlike MDD2 cells.
  • Both cell lines underwent G2/M arrest, but MN-1 cells displayed greater mitochondrial disruption and apoptosis.
  • Flavopiridol treatment reversed the resistance phenotype in MDD2 cells, inducing G1 arrest and inhibiting endoreduplication.

Conclusions:

  • The p53 protein status is a critical determinant of cancer cell sensitivity to TBAs.
  • Differences in the apoptotic cascade, influenced by p53, likely mediate the observed variations in drug sensitivity.
  • Targeting p53 pathways or using combination therapies may overcome TBA resistance in certain cancers.

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