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

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• 作者：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
• 关键词：ULK1 ; Autophagy ; UPR ; Hypoxia
• 刊名：Radiotherapy and Oncology
• 出版年：September, 2013
• 年：2013
• 卷：108
• 期：3
• 页码：529-534
• 全文大小：1095 K

文摘

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 <em>in vitroem> 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伪 dependent manner. ULK1 knockdown decreased autophagy activation, increased mitochondrial 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.