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Title: Investigation of the role of mTORC1 and MAPK/ERK pathways in cellular responses to amino acid deprivation
Author: Wang, Xiaomeng
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2018
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Sustaining proliferative signalling is one of the hallmarks of cancer. Cancer cells universally have high demands for nutrients to support their rapid proliferation. Studies presented in this thesis are focused on mTORC1 and MAPK/ERK signalling pathways, both of which promote cell growth and proliferation and are frequently found over-active in a wide range of cancer types, and their role in response to amino acid deprivation. mTORC1 activation requires GTP-bound Rheb and Rag GTPasemediated lysosomal translocation. TSC2 inhibits mTORC1 by deactivating Rheb and it also undergoes lysosomal translocation. GCN2, a kinase that senses amino acid deficiency, has been identified as a novel regulator of mTORC1 signalling potentially by promoting the lysosomal translocation of TSC2, which inhibits mTORC1 additionally by preventing RagA from associating with lysosomes. We demonstrate that Rheb not only activates the catalytic activity of mTORC1 but also lysosomal translocation of both mTORC1 and TSC2. Therefore, these data suggest an alternative model of mTORC1 inhibition by amino acid deprivation. In addition, we demonstrate that the MAPK/ERK cascade contributes to ferroptosis, an oxidative non-apoptotic cell death, in response to deprivation of the amino acid cystine, via downregulating GPX4 and upregulating NOX4, enzymes known to scavenge and produce lipid ROS respectively. Based on this, amino acid cystine has been identified as a synthetic lethal target in NSCLC cells expressing an activated EGFR mutant, and pharmacological depletion of intracellular cystine using an engineered cystine-degrading enzyme efficiently suppresses tumour growth in a NSCLC xenograft model. These data therefore provide an approach that can be potentially exploited for cancer therapeutics.
Supervisor: Vlatkovic, Nikolina ; Boyd, Mark Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral