Glutamate dehydrogenase 1 mediated glutaminolysis sustains HCC cells proliferation and survival under glucose deprivation

Abstract

Background: It is generally believed that tumor cells could sustain its proliferation and survival under different nutrient status according to a so-called metabolic flexibility. How the metabolic flexibility of glutamine metabolism of HCC cells behaves under different glucose conditions has not yet been fully elucidated. In this study, we investigated how the glutamine metabolism modulate the proliferation and survival of HCC cells in response to different glucose conditions and explored the underlying molecular mechanism.Methods: Two cell lines SK-Hep-1 and PLC/PRF/5 were used to evaluate the glutamine addiction of HCC cells. Then, the cells were cultivated in high glucose medium (25mM glucose) and low glucose medium (1.0 mM glucose), respectively, to investigate whether glutaminolysis changed in response to different glucose levels. And, the underlying mechanism of glutamate dehydrogenase 1 (GDH1) sustaining HCC cells survival under glucose deprivation was explored. Additionally, the underlying correlation of GDH1 and glutamate–oxaloacetate transaminase 1 (GOT1) in glucose -poor HCC tissue was investigated.Results: HCC cells were addicted to glutamine. The glutaminolysis of HCC cells was different in response to different glucose conditions. That is, glutamate transaminases GOT1 involved glutamine metabolism played a dominant role in regulating cell growth when glucose was sufficient, while deaminase GDH1 mediated glutaminolysis became dominant when glucose was limited. Mechanically, low-glucose treated HCC cells could induce an elevated expression of GDH1 to supplement the TCA cycles in respond to glucose deprivation. Additionally, we further uncovered an underlying negative association between GDH1 and GOT1 in HCC tissues with decreased glucose levelsConclusions: GDH1 mediated pathway played a leading role in maintaining cell proliferation and survival under low glucose condition. By contrast, GOT1 mediated pathway was activated under high glucose condition. Mechanically, highly expressed GDH1 could drive the TCA cycle in response to glucose deprivation. Besides, there was a potential negative correlation between GDH1 and GOT1 in glucose-poor HCC tissues.

SKYNET 2023 Conception of the Artificial Super Intelligence Project. A System Approach. ver. 3

“… Self-Rewarding Language Models [Yuan et al (2024)] -feedback at the meta-level of control  An Interactive Agent Foundation Model [Durante et al (2024)] -target management and regulation  Large Language Models LLMs Self-Compose Reasoning Structures [Zhou et al (2024)] -built-in set of standard intelligent algorithms  Large Action Models, LAMs [Thomas (2024)] -agency and purposeful behavior  Machine Culture [Brinkmann et al (2023)] -AI-agents are already being included in Intertext  Simulacra as Conscious Exotica [Shanahan (2024)] -AGI won't be anthropomorphic  Principled Limitations on Self-Representation for Generic Physical Systems [Fields, Glazebrook & Levin (2024)] -internal modeling is not enough -multi-agent systems MASs are needed  A Guide for Navigating AI. Developments in 2024 [DGA-ASG (2024)] -continued growing importance of the AI topic in the world.…”

“…Our approach provides a promising avenue for developing generalist, actiontaking, multimodal systems. [Zhou et al (2024)] -SELF-DISCOVER: Large Language Models Self-Compose Reasoning Structures…”