p53 status determines the role of autophagy in pancreatic tumour development

Mathias T. Rosenfeldt, Jim O’Prey, Jennifer P. Morton, Colin Nixon, Gillian MacKay, Agata Mrowinska, Amy Au, Taranjit Singh Rai, Liang Zheng, Rachel Ridgway, Peter D. Adams, Kurt I. Anderson, Eyal Gottlieb, Owen J. Sansom & Kevin M. Ryan

Nature. 2013. 504 (7479): 296-300.

Speaker: Wan-Ting Kuo (郭琬婷)                                       Time: 14:00~15:00, Mar. 5, 2014

Commentator: Dr. Chih-Peng Chang (張志鵬老師)            Place: Room 601

Abstract:

Autophagy, a degradation and recycling process, forms autophagosome and fuses with lysosome to become autolysosome for degradation of cytoplasmic constituents. Autophagy plays a major role in cellular homeostasis. Furthermore, autophagy either promotes or suppresses tumorigenesis (1) (2). Here, the authors clarified the role between autophagy and p53 in pancreatic ductal adenocarcinoma (PDAC) development. They established a humanized and genetically modified mouse model of PDAC, which harbors a mutant K-ras oncogene together with autophagy deficiency (Atg5 or Atg7 gene knockout). They found that these mice exhibited accumulation of p53 and the role of autophagy in tumor development is connected to p53. These mice with autophagy deficiency and mutant K-ras in their pancreases only developed low-grade, pre-malignant pancreatic intraepithelial neoplasia (PanIN). In contrast, in the mice with mutant K-ras and lacking p53 as well as autophagy tumor development was accelerated. Metabolic analysis showed that glucose uptake was enhanced accompanied with enrichment of anabolic pathways which provide the energy for tumor growth. In conclusion, this study showed that the changes in metabolism in PDACs caused by autophagy deficiency are associated with p53 loss and may be a response to increased aggressiveness of the tumor. These findings clearly show that p53 status switches the role of autophagy during pancreatic tumor development, highlighting important considerations for the treatment of malignant disease.

References:

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2. Kroemer G, Marino G and Levine B. Autophagy and the integrated stress response. Mol Cell. 2010; 40: 280–293.