Elucidating mechanisms underlying cancer cell regulation of serine synthesis

• Main Author: Ong, Jean Xin Ying
• Other Authors: -
• Format: Final Year Project
• Language: English
• Published: Nanyang Technological University 2024
• Subjects: Medicine, Health and Life Sciences
• Online Access: https://hdl.handle.net/10356/176243
• Institution: Nanyang Technological University

Natural killer/T-cell lymphoma (NKTL) is a highly aggressive form of Epstein-Barr virus (EBV) associated non-Hodgkin lymphoma (NHL) with dismal treatment outcomes observed in advanced stages. Previous research conducted in our laboratory revealed that activating transcription factor 4 (ATF4) and phosphoglycerate dehydrogenase (PHGDH) were not expressed in NKTL even under conditions of serine deprivation, despite the absence of mutations in general control non-derepressible 2 (GCN2), one of four known eukaryotic translation initiation factor 2 alpha (eIF2) kinases. It was hypothesised that the de novo serine synthesis (DNSS) pathway was silenced, making NKTL particularly sensitive to extracellular serine levels. In this study, we plan to uncover the mechanisms behind the suppression of DNSS by examining the various kinases and their involvement in downstream signalling within the integrated stress response (ISR). Drug activators targeting different eIF2 kinases were utilised to induce ISR in NKS1. Our findings indicate a significant increase in ATF4 expression in NKS1 following exposure to the small-molecular HRI-activator drug, BtdCPU. Through activation of the HRI-phospho-eIF2-ATF4 pathway, we successfully enhanced DNSS levels in NKS1. By comprehensively analysing this pathway, our objective is to elucidate the metabolic adaptations present in NKTLs and contribute to the advancement of understanding in ISR biology.