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Metabolic pathways and the unfolded protein response

Prostate cancer cells experience high proliferative rates and high metabolic demand [REF] requiring high protein turnover and synthesis occurring in the Endoplasmic Reticulum (ER). Misfolded protein accumulation causes ER stress, which the UPR resolves through increased ER associated degradation (ERAD), translational cessation and increased folding capacity/protein clearance. Continued androgen receptor (AR) signalling remains critical throughout, however a number of other important oncogenic transcription factors also regulate and depend on metabolic reprogramming and the unfolded protein response to promote tumorigenesis [REF].  In a collaboration with Lisa Butler in Adelaide we have recently identified two important metabolic enzymes that support androgen receptor-driven tumorigenesis – one is associated with fatty acid elongation (ELOVL5) [16] and the other with the pentose phosphate shunt pathway sustaining nucleotide metabolism and redox balance (6PGD) [17].  We have also further investigated the function of a kinase, CAMKK2, that we have previously shown to be relevant in both androgen receptor-dependent and -independent disease. Importantly we find that it sustains cancer cell proliferation by maintaining the integrity of the secretory pathway and lysosomal function [18]. The latter is important for mTORC activity and metabolite turnover to support protein synthesis and mitochondrial function. This suggests that CAMKK2 activity may predict responses to mTORC inhibitors, a number of which have progressed to clinical trials. We have also embarked on a study to determine how IRE1 activity, an important regulator of one axis of the unfolded protein response, affects other important drivers of tumorigenesis such as lineage plasticity.  This work is led by Dr Dimitrios Doultsinos who recently obtained a PCF/CRIS Cancer Foundation/Larry Leeds/ Eustace Wolfington Young Investigator Award to further develop an IRE1 activity signature as a proxy of multiple key PCa biologies [REF] as well as evaluate the cross-talk between IRE1 activity and microRNA-346, a regulator of the DNA damage response [REF].  Dr. Claire Fletcher (Imperial College, London) is a mentor on this project and led the prior work on microRNA-346 funded by a John Black Foundation/PCF Challenge Award. This work has a strong translational component as it aims to validate novel treatment combinations as well as tools to predict such treatments.