PCK1 dysregulation in cancer: Metabolic reprogramming, oncogenic activation, and therapeutic opportunities

The last few decades have witnessed an advancement in our understanding of mul-tiple cancer cell pathways related to metabolic reprogramming. One of the most important cancer hallmarks, including aerobic glycolysis (the Warburg effect), the central carbon pathway, and multiple-branch metabolic pathway remodeling, enables tumor growth, progres-sion, and metastasis. Phosphoenolpyruvate carboxykinase 1 (PCK1), a key rate-limiting enzyme in gluconeogenesis, catalyzes the conversion of oxaloacetate to phosphoenolpyruvate. PCK1 expression in gluconeogenic tissues is tightly regulated during fasting. In tumor cells, PCK1 is regulated in a cell-autonomous manner rather than by hormones or nutrients in the extracel-lular environment. Interestingly, PCK1 has an anti-oncogenic role in gluconeogenic organs (the liver and kidneys), but a tumor-promoting role in cancers arising from non-gluconeogenic or-gans. Recent studies have revealed that PCK1 has metabolic and non-metabolic roles in mul-tiple signaling networks linking metabolic and oncogenic pathways. Aberrant PCK1 expression results in the activation of oncogenic pathways, accompanied by metabolic repro-gramming, to maintain tumorigenesis. In this review, we summarize the mechanisms underly-ing PCK1 expression and regulation, and clarify the crosstalk between aberrant PCK1 expression, metabolic rewiring, and signaling pathway activation. In addition, we highlight the clinical relevance of PCK1 and its value as a putative cancer therapeutic target.(c) 2022 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co., Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons. org/licenses/by-nc-nd/4.0/).