title: Induction of autophagy by drug-resistant esophageal cancer cells promotes their survival and recovery following treatment with chemotherapeutics.
abstract: We investigated the cell-death mechanisms induced in esophageal cancer cells in response to the chemotherapeutic drugs, 5-fluorouracil (5-FU) and cisplatin. Chemosensitive cell lines exhibited apoptosis whereas chemoresistant populations exhibited autophagy and a morphology resembling type II programmed cell death (PCD). Cell populations that respond with autophagy are more resistant and will recover following withdrawal of the chemotherapeutic agents. Specific inhibition of early autophagy induction with siRNA targeted to Beclin 1 and ATG7 significantly enhanced the effect of 5-FU and reduced the recovery of drug-treated cells. Pharmacological inhibitors of autophagy were evaluated for their ability to improve chemotherapeutic effect. The PtdIns 3-kinase inhibitor 3-methyladenine did not enhance the cytotoxicity of 5-FU. Disruption of lysosomal activity with bafilomycin A 1 or chloroquine caused extensive vesicular accumulation but did not improve chemotherapeutic effect. These observations suggest that an autophagic response to chemotherapy is a survival mechanism that promotes chemoresistance and recovery and that selective inhibition of autophagy regulators has the potential to improve chemotherapeutic regimes. Currently available indirect inhibitors of autophagy are, however, ineffective at modulating chemosensitivity in these esophageal cancer cell lines.
authors.affiliation: Leslie C. Quick Laboratory, Cork Cancer Research Centre, BioSciences Institute, University College Cork and Mercy University Hospital, Cork, Ireland.
authors.forename: Tracey R
authors.initials: TR
authors.lastname: O'Donovan
authors.forename: Gerald C
authors.initials: GC
authors.lastname: O'Sullivan
authors.forename: Sharon L
authors.initials: SL
authors.lastname: McKenna
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology / Q000534:rehabilitation; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D001343:Autophagy / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000534:rehabilitation; D053148:Caspase 3 / Q000378:metabolism; D002470:Cell Survival / Q000235:genetics; D002945:Cisplatin / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000534:rehabilitation; D005472:Fluorouracil / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D020127:Recovery of Function / Q000235:genetics; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000235:genetics / Q000502:physiology
chemical_list: C505407:CASP3 protein, human; D053148:Caspase 3; D002945:Cisplatin; D005472:Fluorouracil