Role of TFEB-driven autophagy regulation in pancreatic cancer treatment

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

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.

Details

Original languageEnglish
Pages (from-to)164-172
Number of pages9
JournalInternational Journal of Oncology
Volume49
Issue number1
Publication statusPublished - Jul 2016
Peer-reviewedYes

External IDs

Scopus 84978437158
PubMed 27175909

Keywords

Sustainable Development Goals

Keywords

  • Animals, Apoptosis/drug effects, Autophagy/drug effects, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/biosynthesis, Carcinoma, Pancreatic Ductal/drug therapy, Cell Line, Tumor, Deoxycytidine/administration & dosage, Female, Gene Expression Regulation, Neoplastic/drug effects, Gene Knockout Techniques, Humans, Lysosomes/genetics, Male, Mice, Proto-Oncogene Proteins p21(ras)/biosynthesis, RNA Interference, Gemcitabine