Autophagy mediates epithelial cancer chemoresistance by reducing p62/SQSTM1 accumulation

RA Battista, M Resnati, C Facchi, E Ruggieri, F Cremasco, F Paradiso, U Orfanelli, L Giordano, M Bussi, S Cenci, E Milan

Research output: Contribution to journalArticle

Abstract

To cope with intrinsic and environmental stress, cancer cells rely on adaptive pathways more than non-transformed counterparts. Such non-oncogene addiction offers new therapeutic targets and strategies to overcome chemoresistance. In an attempt to study the role of adaptive pathways in acquired drug resistance in carcinoma cells, we devised a model of in vitro conditioning to three standard chemotherapeutic agents, cisplatin, 5-fluorouracil, and docetaxel, from the epithelial cancer cell line, HEp-2, and investigated the mechanisms underlying reduced drug sensitivity. We found that triple-resistant cells suffered from higher levels of oxidative stress, and showed heightened anti-stress responses, including the antioxidant Nrf2 pathway and autophagy, a conserved pleiotropic homeostatic strategy, mediating the clearance of aggregates marked by the adapter p62/SQSTM1. As a result, re-administration of chemotherapeutic agents failed to induce further accumulation of reactive oxygen species and p62. Moreover, autophagy proved responsible for chemoresistance through the avoidance of p62 accumulation into toxic protein aggregates. Indeed, p62 ablation was sufficient to confer resistance in parental cells, and genetic and pharmacological autophagic inhibition restored drug sensitivity in resistant cells in a p62-dependent manner. Finally, exogenous expression of mutant p62 lacking the ubiquitin- and LC3-binding domains, required for autophagic engulfment, increased chemosensitivity in TDR HEp-2 cells. Altogether, these findings offer a cellular system to investigate the bases of acquired chemoresistance of epithelial cancers and encourage challenging the prognostic and anti-neoplastic therapeutic potential of p62 toxicity. © 2018 Battista et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Original languageEnglish
Article numbere0201621
JournalPLoS One
Volume13
Issue number8
DOIs
Publication statusPublished - 2018

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autophagy
Autophagy
Cells
docetaxel
neoplasms
Pharmaceutical Preparations
Neoplasms
Oxidative stress
Poisons
cells
Ubiquitin
Ablation
Fluorouracil
Cisplatin
Toxicity
Reactive Oxygen Species
fluorouracil
Antioxidants
drugs
therapeutics

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Autophagy mediates epithelial cancer chemoresistance by reducing p62/SQSTM1 accumulation. / Battista, RA; Resnati, M; Facchi, C; Ruggieri, E; Cremasco, F; Paradiso, F; Orfanelli, U; Giordano, L; Bussi, M; Cenci, S; Milan, E.

In: PLoS One, Vol. 13, No. 8, e0201621, 2018.

Research output: Contribution to journalArticle

Battista, RA ; Resnati, M ; Facchi, C ; Ruggieri, E ; Cremasco, F ; Paradiso, F ; Orfanelli, U ; Giordano, L ; Bussi, M ; Cenci, S ; Milan, E. / Autophagy mediates epithelial cancer chemoresistance by reducing p62/SQSTM1 accumulation. In: PLoS One. 2018 ; Vol. 13, No. 8.
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