title: Paclitaxel-resistant cancer cell-derived secretomes elicit ABCB1-associated docetaxel cross-resistance and escape from apoptosis through FOXO3a-driven glycolytic regulation.
abstract: Chemotherapy-induced cancer cell secretomes promote resistance due, in part, to a predominant glycolytic energy metabolism, which drives aggressive cancer cell proliferation. However, the characterization of these secretomes and the molecular events that associate them with acquired drug resistance remain poorly understood. In this study, we show that secretomes of cancer cells with high-level paclitaxel resistance stimulated cell proliferation and suppressed drug-induced apoptosis of drug-sensitive cells. We also found that drug (docetaxel)-stimulated induction of interferon-α (IFN-α), IFN-λ and tumor necrosis factor-α (TNF-α) release in drug-sensitive cells was lowered by these secretomes. The promotion of cell proliferation by paclitaxel-resistant (PacR) cancer cell secretomes was associated, in part, with an increase in S phase of the cell cycle and downregulation of the cell death pathway that supports escape from apoptosis. In addition, we also found that the regulation of targeted glycolysis in PacR cancer cells alters the effects of the secretomes on cell growth, apoptosis, ATP generation and acquired drug resistance. Further study revealed that the deletion of FOXO3a transcription exacerbates glycolytic shift-induced apoptosis by rescuing TRAIL expression. By generating a docetaxel-cross-resistant PacR cancer cell line (PacR/DCT), we further clarified the role of FOXO3a in glycolysis-associated mediation of P-glycoprotein/ABCB1 hyperactivity that induces docetaxel cross-resistance. These findings suggest that suppression of the cellular energy supply by targeting glycolysis may inhibit the multiplicity of acquired chemotherapy resistance. Therefore, the therapeutic inhibition of FOXO3a might direct glycolysis to induce apoptosis and overcome multidrug resistance in cancer cells.
authors.affiliation: College of Pharmacy, Seoul National University, Seoul, Korea.|Department of Biochemistry, College of Veterinary Medicine, Seoul National University, Seoul, Korea.
authors.forename: Mark Borris D
authors.initials: MB
authors.lastname: Aldonza
authors.affiliation: College of Pharmacy, Seoul National University, Seoul, Korea.
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Hong
authors.affiliation: College of Pharmacy, Seoul National University, Seoul, Korea.
authors.forename: Sang Kook
authors.initials: SK
authors.lastname: Lee
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000255:Adenosine Triphosphate / Q000378:metabolism; D017209:Apoptosis / Q000235:genetics*; D045744:Cell Line, Tumor; D055252:Cell-Derived Microparticles / Q000378:metabolism*; D000077143:Docetaxel; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D000071316:Forkhead Box Protein O3 / Q000235:genetics* / Q000378:metabolism; D020868:Gene Silencing; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis; D006801:Humans; D016898:Interferon-alpha / Q000096:biosynthesis; D007372:Interferons / Q000096:biosynthesis; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism*; D017239:Paclitaxel / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D022142:Secretory Vesicles / Q000378:metabolism*; D015398:Signal Transduction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D043823:Taxoids / Q000494:pharmacology; D007378:Interleukins; D000095022:Interferon Lambda
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000255:Adenosine Triphosphate; D000077143:Docetaxel; D000071316:Forkhead Box Protein O3; D005947:Glucose; D016898:Interferon-alpha; D007372:Interferons; D017239:Paclitaxel; D051057:Proto-Oncogene Proteins c-akt; D053221:TNF-Related Apoptosis-Inducing Ligand; D043823:Taxoids; C513055:ABCB1 protein, human; C499517:FOXO3 protein, human; C505653:TNFSF10 protein, human; C000624353:interferon-lambda, human; D007378:Interleukins; D000095022:Interferon Lambda