Autophagy mediates epithelial cancer chemoresistance by reducing p62/SQSTM1 accumulation

• Published in: PloS one Vol. 13; no. 8; p. e0201621
• Main Authors: Battista, R. Alessia, Resnati, Massimo, Facchi, Cecilia, Ruggieri, Elena, Cremasco, Floriana, Paradiso, Francesca, Orfanelli, Ugo, Giordano, Leone, Bussi, Mario, Cenci, Simone, Milan, Enrico
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.08.2018; Public Library of Science (PLoS)
• Subjects: 5-Fluorouracil; Accumulation; Adapters; Addictions; Age; Aggregates; Antineoplastic agents; Antineoplastic Agents - pharmacology; Antioxidants; Autophagy; Autophagy (Cytology); Biology; Biology and Life Sciences; Cancer; Cancer therapies; Cell death; Cell Line, Tumor; Chemoresistance; Chemotherapy; Cisplatin; Cisplatin - pharmacology; Docetaxel - pharmacology; Down-Regulation; Drug resistance; Drug Resistance, Neoplasm; Environmental stress; Epithelial cells; Fluorouracil - pharmacology; Gene Expression Regulation, Neoplastic - drug effects; Genetics; Humans; Kinases; Medical prognosis; Medicine and Health Sciences; Mutation; Neoplasms, Glandular and Epithelial - genetics; Neoplasms, Glandular and Epithelial - metabolism; Otolaryngology; Oxidation resistance; Oxidative Stress; Oxygen; Phagocytosis; Pharmacology; Protein Domains; Proteins; Reactive oxygen species; Research and analysis methods; Sensitivity; Sequestosome-1 Protein - chemistry; Sequestosome-1 Protein - genetics; Sequestosome-1 Protein - metabolism; Stress response; Therapeutic applications; Toxicity; Transcription factors; Tumorigenesis; Ubiquitin; Italy
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0201621

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 antineoplastic therapeutic potential of p62 toxicity.