Role of TFEB-driven autophagy regulation in pancreatic cancer treatment

  • Authors:
    • Kathrin Klein
    • Kristin Werner
    • Christian Teske
    • Miriam Schenk
    • Thomas Giese
    • Jürgen Weitz
    • Thilo Welsch
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  • Published online on: May 5, 2016     https://doi.org/10.3892/ijo.2016.3505
  • Pages: 164-172
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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.
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July-2016
Volume 49 Issue 1

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Klein K, Werner K, Teske C, Schenk M, Giese T, Weitz J and Welsch T: Role of TFEB-driven autophagy regulation in pancreatic cancer treatment. Int J Oncol 49: 164-172, 2016
APA
Klein, K., Werner, K., Teske, C., Schenk, M., Giese, T., Weitz, J., & Welsch, T. (2016). Role of TFEB-driven autophagy regulation in pancreatic cancer treatment. International Journal of Oncology, 49, 164-172. https://doi.org/10.3892/ijo.2016.3505
MLA
Klein, K., Werner, K., Teske, C., Schenk, M., Giese, T., Weitz, J., Welsch, T."Role of TFEB-driven autophagy regulation in pancreatic cancer treatment". International Journal of Oncology 49.1 (2016): 164-172.
Chicago
Klein, K., Werner, K., Teske, C., Schenk, M., Giese, T., Weitz, J., Welsch, T."Role of TFEB-driven autophagy regulation in pancreatic cancer treatment". International Journal of Oncology 49, no. 1 (2016): 164-172. https://doi.org/10.3892/ijo.2016.3505