Defining an acetyl-CoA sensing mechanism as a form of inter-organelle communication in cancer

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PROJECT SUMMARY Cancer cells are subjected to variable and often severely nutrient-limited microenvironments to which they must adapt in order to survive. In addition, effective therapeutic targeting of cancer metabolism requires an understanding of the compensatory networks and mechanisms of metabolic flexibility that are engaged when a metabolic enzyme is inhibited. In order for cells to activate compensatory mechanisms, they must first be able to detect a metabolic deficiency. This is exemplified by AMP-activated protein kinase (AMPK), which senses a rise in the AMP/ATP ratio and mediates signaling effects to reduce ATP consumption and enhance ATP production. Abundant evidence now indicates that acetyl-CoA is also a key metabolite that is closely monitored by cells and that adaptive mechanisms are engaged when its availability is limited. Moreover, ongoing clinical trials indicate that a therapeutic window exists for targeting the acetyl-CoA producing enzyme ATP-citrate lyase (ACLY), at least in the liver. We previously reported that in response to ACLY inhibition or Acly genetic deletion, the enzyme acyl-CoA synthetase short-chain family member 2 (ACSS2), which generates acetyl-CoA from acetate, is upregulated and supports cell viability and proliferation. Moreover, acetate, which is normally dispensable for cells, becomes essential for survival in the absence of ACLY. However, the mechanisms through which cells sense a deficiency in acetyl-CoA and implement this adaptive response remain unknown. In this grant application, building on published and preliminary data and leveraging reagents generated in our lab and the metabolomics and proteomics expertise of our long-time collaborators, we propose an approach to address the fundamental question of how cells sense acetyl-CoA. We hypothesize that acetyl-CoA sensing requires close intraorganelle communication between the mitochondria, cytosol, endoplasmic reticulum, and nucleus. We will: 1) determine the subcellular location at which acetyl-CoA production is sensed to promote ACSS2 upregulation; 2) define the mechanisms through which acetyl-CoA insufficiency is sensed to induce ACSS2 upregulation; and 3) identify the functions of nuclear-cytosolic acetyl-CoA that are essential for viability. Findings from this study will both define fundamental mechanisms of nutrient sensing and inform optimal approaches for targeting acetyl-CoA metabolism therapeutically.