Autophagy is the process by which different organelles in a cell are degraded into their cellular building blocks. During degradation, organelles are surrounded by a lipid membrane prior to fusion with lysosomes where they are broken down. This gives a cell an alternative to apoptosis (cell death) where it can use these building blocks to survive or it can degrade organelles which have become damaged. It has a very complex role in the cell and specifically in cancer, where it has been shown to both promote and suppress tumour formation. Recent research completed at Glasgow University has shown autophagy to be very important in the development of Pancreatic Ductal Adenocarcinoma (PDAC), with particular relevance to the transcription factor p53.
What is Pancreatic Ductal Adenocarcinoma?
Pancreatic ductal adenocarcinoma is an extremely aggressive form of pancreatic cancer which reduces a person’s life span to less than 5 years. As this cancer has very few symptoms, it’s usually not caught before it is very advanced and has metastasised to other parts of the body. Before progression to fully blown PDAC a patient first develops precursor lesions, which essentially are less severe versions of the cancer that form on the pancreas. Over time with further mutations these will develop into full PDAC.
The most common mutation that causes one of these types of precursor lesion is the mutation of the Kras gene which encodes for a protein involved a number of different processes such as cell growth, differentiation and proliferation. Eventually these cells will acquire more mutations which make them more cancerous.
How does Autophagy fit into all of this?
Interestingly, the research completed at Glasgow University has shown that inactivation of certain genes involved in autophagy results in the blocking of tumour progression from precursor lesions into full PDAC. The team first investigated deletion of the genes ATG7 and ATG5 (which are required for autophagy) in normal mice without Kras mutations. The deletion of these genes caused destruction of pancreatic tissue and killed 60% of the mice which were being investigated by the study.
The same experiment was also conducted on mice with mutated Kras. In wild type mice, this mutation will cause precursor lesions to form which will then progress into PDAC. In mice without ATG7 (and thus autophagy) precursor lesions still formed but they did not progress any further. This halt in progression was shown to be due to activation of p53, a transcription factor whose mutation is found in a number of different cancers, and 50% of human PDAC. p53 plays a key role in apoptosis, so when autophagy is inhibited by deletion of ATG5/7 then cells instead stop growing and replicating or die (thus stopping the tumours from progressing). Interestingly, it was shown that while ATG5 and 7 are needed when p53 is present in the cell for tumours to form and progress to PDAC, if p53 is deleted then these will instead inhibit tumour formation. p53 is therefore a key component in tumour development and cell fate.
So the previous experiments have shown that autophagy is critical for tumour development in mice with Kras mutations. But this is not true when p53 is absent- Why is this?
Further experiments showed that when p53 was deleted the cell becomes less dependent on autophagy. Mitochondria are the power station of the cell and generate energy as ATP by the process of oxidative phosphorylation. The only way in which these organelles can be broken down is by autophagy. p53 will normally increase the amount of oxidative phosphorylation occurring in the mitochondria and suppress formation of ATP by glycolysis (oxidative phosphorylation is much more efficient at producing ATP to power the cell). Loss of p53 therefore causes decreased oxidative phosphorylation, putting less strain on the mitochondria to produce ATP. As mitochondria are less active, it is less important that they are degraded by autophagy.
Why do tumours form more quickly in p53 null cells?
Glucose is broken down during the process of glycolysis, but can form a number of intermediates which cause tumours to grow more quickly. If you delete p53 and increase glycolysis, then you are generating more of these intermediates. This is why if you have mutated Kras (to form precursor lesions) and then loss of p53, tumours grow very quickly and aggressively giving PDAC patients such a poor prognosis.
Rosenfeldt MT, O’Prey J, Morton JP, Nixon C, Mackay G, Mrowinska A, Au A, Rai TS, Zheng L, Ridgway R, Adams PD, Anderson KI, Gottlieb E, Sansom OJ, & Ryan KM (2013). p53 status determines the role of autophagy in pancreatic tumour development. Nature PMID: 24305049