Phatak, V. et al. (2021) Mutant p53 promotes RCP-dependent chemoresistance coinciding with increased delivery of P-glycoprotein to the plasma membrane. Cell Death and Disease, 12(2), 207. (doi: 10.1038/s41419-021-03497-y) (PMID:33627632) (PMCID:PMC7904762)
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Abstract
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.
Item Type: | Articles |
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Additional Information: | Funding information S.Z. is funded by Cancer Research UK (A29800 to SZ) and CRUK Beatson Institute core funding (A17196). P.M., Y.vG. and V.P. were funded through a HDF fellowship (WT101242AIA) of the Welcome Trust (end date March 2019). P. M. and Y.vG. are further supported by the CRUK and the University of Manchester. |
Status: | Published |
Refereed: | Yes |
Glasgow Author(s) Enlighten ID: | Le Quesne, Professor John |
Authors: | Phatak, V., von Grabowiecki, Y., Janus, J., Officer, L., Behan, C., Aschauer, L., Pinon, L., Mackay, H., Zanivan, S., Norman, J. C., Kelly, M., Le Quesne, J., and Muller, P. A. J. |
College/School: | College of Medical Veterinary and Life Sciences > School of Cancer Sciences |
Journal Name: | Cell Death and Disease |
Publisher: | Springer Nature |
ISSN: | 2041-4889 |
ISSN (Online): | 2041-4889 |
Copyright Holders: | Copyright © 2021 The Authors |
First Published: | First published in Cell Death and Disease 12:207 |
Publisher Policy: | Reproduced under a Creative Commons licence |
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