The last few decades have witnessed an advancement in our understanding of multiple 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

progression

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 extracellular 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 organs. Recent studies have revealed that PCK1 has metabolic and non-metabolic roles in multiple signaling networks linking metabolic and oncogenic pathways. Aberrant PCK1 expression results in the activation of oncogenic pathways

accompanied by metabolic reprogramming

to maintain tumorigenesis. In this review

we summarize the mechanisms underlying 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.