Mutant p53 promotes RCP-dependent chemoresistance coinciding with increased delivery of P-glycoprotein to the plasma membrane

Cell Death Dis. 2021 Feb 24;12(2):207. doi: 10.1038/s41419-021-03497-y.


TP53 is the most frequently mutated gene in cancers. Mutations lead to loss of p53 expression or expression of a mutant protein. Mutant p53 proteins commonly lose wild-type function, but can also acquire novel functions in promoting metastasis and chemoresistance. Previously, we uncovered a role for Rab-coupling protein (RCP) in mutant p53-dependent invasion. RCP promotes endosomal recycling and signalling of integrins and receptor tyrosine kinases. In a screen to identify novel RCP-interacting proteins, we discovered P-glycoprotein (P-gp). Thus, we hypothesised that mutant p53 could promote chemoresistance through RCP-dependent recycling of P-gp. The interaction between RCP and P-gp was verified endogenously and loss of RCP or mutant p53 rendered cells more sensitive to cisplatin and etoposide. In mutant p53 cells we detected an RCP-dependent delivery of P-gp to the plasma membrane upon drug treatment and decreased retention of P-gp substrates. A co-localisation of P-gp and RCP was seen in mutant p53 cells, but not in p53-null cells upon chemotherapeutic exposure. In conclusion, mutant p53 expression enhanced co-localisation of P-gp and RCP to allow for rapid delivery of P-gp to the plasma membrane and increased resistance to chemotherapeutics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / genetics
  • ATP Binding Cassette Transporter, Subfamily B / metabolism*
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacology*
  • Cell Membrane / drug effects*
  • Cell Membrane / genetics
  • Cell Membrane / metabolism
  • Cell Membrane / pathology
  • Cisplatin / pharmacology
  • Dose-Response Relationship, Drug
  • Drug Resistance, Neoplasm* / genetics
  • Etoposide / pharmacology
  • HCT116 Cells
  • Humans
  • Male
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice, Inbred BALB C
  • Mice, Nude
  • Mutation*
  • Neoplasms / drug therapy*
  • Neoplasms / genetics
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Tumor Burden / drug effects
  • Tumor Suppressor Protein p53 / genetics*
  • Tumor Suppressor Protein p53 / metabolism
  • Xenograft Model Antitumor Assays


  • ATP Binding Cassette Transporter, Subfamily B
  • Adaptor Proteins, Signal Transducing
  • Antineoplastic Agents
  • Membrane Proteins
  • RAB11FIP1 protein, human
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Etoposide
  • Cisplatin