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

Autor: Phatak V; MRC Toxicology Unit, University of Cambridge, Cambridge, UK.; Avacta Life Sciences, Cambridge, UK., von Grabowiecki Y; Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK., Janus J; Centre for Core Biotechnology Services, University of Leicester, Leicester, UK., Officer L; MRC Toxicology Unit, University of Cambridge, Cambridge, UK., Behan C; Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK., Aschauer L; MRC Toxicology Unit, University of Cambridge, Cambridge, UK., Pinon L; MRC Toxicology Unit, University of Cambridge, Cambridge, UK., Mackay H; MRC Toxicology Unit, University of Cambridge, Cambridge, UK.; Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK., Zanivan S; Cancer Research UK, Beatson Institute, Glasgow, UK.; Institute of Cancer Sciences, University of Glasgow, Glasgow, UK., Norman JC; Cancer Research UK, Beatson Institute, Glasgow, UK., Kelly M; Centre for Core Biotechnology Services, University of Leicester, Leicester, UK., Le Quesne J; MRC Toxicology Unit, University of Cambridge, Cambridge, UK.; Leicester Cancer Research Centre, University of Leicester, Leicester, UK., Muller PAJ; MRC Toxicology Unit, University of Cambridge, Cambridge, UK. Patricia.Muller@CRUK.Manchester.ac.uk.; Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK. Patricia.Muller@CRUK.Manchester.ac.uk.
Jazyk: angličtina
Zdroj: Cell death & disease [Cell Death Dis] 2021 Feb 24; Vol. 12 (2), pp. 207. Date of Electronic Publication: 2021 Feb 24.
DOI: 10.1038/s41419-021-03497-y
Abstrakt: 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.
Databáze: MEDLINE
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