title: Role of TFEB-driven autophagy regulation in pancreatic cancer treatment.
abstract: Autophagy pathways promote the growth of pancreatic ductal adenocarcinoma (PDAC), but the critical role is yet to be determined. Transcription factor EB (TFEB) centrally controls lysosomal and autophagy biogenesis. This study aimed to explore the role of TFEB for autophagy regulation in PDAC. We found that TFEB expression was significantly elevated in human PDAC samples (n=45), and localized to the cytoplasm and nucleus in 11 of 15 cases. In primary PDAC cell lines, TFEB nuclear expression was evident even under basal conditions, and further nuclear enrichment was achieved by starvation. Transient RNA interference reduced TFEB expression to 11-23%, but starvation-induced accumulation of the lipidated, autophagosome-associated LC3-II and the autophago-to-lysosome route was maintained after TFEB silencing. Likewise, gemcitabine treatment of the cancer cells augmented apoptosis and LC3-II as an indicator of autophagy, regardless of the TFEB expression levels. Moreover, the interplay of oncogenic KRAS with TFEB and autophagy was investigated. KRAS silencing caused PDAC cell apoptosis and a reciprocal increase in TFEB expression. This inverse correlation could be confirmed in published data sets of genetically engineered mouse models and human PDAC samples using the the Pubmed GEO and BioPortal databases, and was independent of KRAS mutation status. In conclusion, the central autophagy regulator TFEB is expressed and active in PDAC, but autophagy is sustained after TFEB knockdown, suggesting alternative bypass signaling. TFEB is dispensable for gemcitabine-induced cell death, but inversely correlated with KRAS expression.
authors.affiliation: Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, D-01307 Dresden, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Klein
authors.affiliation: Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, D-01307 Dresden, Germany.
authors.forename: Kristin
authors.initials: K
authors.lastname: Werner
authors.affiliation: Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, D-01307 Dresden, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Teske
authors.affiliation: Department of General, Visceral and Transplantation Surgery, University of Heidelberg, D-69120 Heidelberg, Germany.
authors.forename: Miriam
authors.initials: M
authors.lastname: Schenk
authors.affiliation: Institute for Immunology, University of Heidelberg, D-69120 Heidelberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Giese
authors.affiliation: Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, D-01307 Dresden, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Weitz
authors.affiliation: Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, D-01307 Dresden, Germany.
authors.forename: Thilo
authors.initials: T
authors.lastname: Welsch
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects*; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055786:Gene Knockout Techniques; D006801:Humans; D008247:Lysosomes / Q000235:genetics; D008297:Male; D051379:Mice; D016283:Proto-Oncogene Proteins p21(ras) / Q000096:biosynthesis / Q000235:genetics*; D034622:RNA Interference; D000093542:Gemcitabine
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C117307:KRAS protein, human; C064972:TFEB protein, human; D003841:Deoxycytidine; D016283:Proto-Oncogene Proteins p21(ras); D000093542:Gemcitabine