The autophagy associated gene, ULK1, promotes tolerance to chronic and acute hypoxia

Marco B. E. Schaaf, Dan Cojocari, Tom G. Keulers, Barry Jutten, Maud H. Starmans, Monique C. de Jong, Adrian C. Begg, Kim G. M. Savelkouls, Johan Bussink, Marc Vooijs, Bradly G. Wouters, Kasper M. A. Rouschop*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

36 Citations (Web of Science)

Abstract

Background and purpose: Tumor hypoxia is associated with therapy resistance and malignancy. Previously we demonstrated that activation of autophagy and the unfolded protein response (UPR) promote hypoxia tolerance. Here we explored the importance of ULK1 in hypoxia tolerance, autophagy induction and its prognostic value for recurrence after treatment. Material and methods: Hypoxic regulation of ULK1 mRNA and protein was assessed in vitro and in primary human head and neck squamous cell carcinoma (HNSCC) xenografts. Its importance in autophagy induction, mitochondrial homeostasis and tolerance to chronic and acute hypoxia was evaluated in ULK1 knockdown cells. The prognostic value of ULK1 mRNA expression was assessed in 82 HNSCC patients. Results: ULK1 enrichment was observed in hypoxic tumor regions. High enrichment was associated with a high hypoxic fraction. In line with these findings, high ULK1 expression in HNSCC patients appeared associated with poor local control. Exposure of cells to hypoxia induced ULK1 mRNA in a UPR and HIF1 alpha dependent manner. ULK1 knockdown decreased autophagy activation, increased mitochondria] mass and ROS exposure and sensitized cells to acute and chronic hypoxia. Conclusions: We demonstrate that ULK1 is a hypoxia regulated gene and is associated with hypoxia tolerance and a worse clinical outcome.
Original languageEnglish
Pages (from-to)529-534
JournalRadiotherapy and Oncology
Volume108
Issue number3
DOIs
Publication statusPublished - Sep 2013

Keywords

  • ULK1
  • Autophagy
  • UPR
  • Hypoxia

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