NUAK isoforms promote glucose and glutamine metabolic reprogramming driven colon cancer progression and migration through regulation of AMPK/mTOR signaling.

Colorectal cancer (CRC) cells undergo significant alterations in glucose and glutamine metabolism to support rapid growth and migration. However, the molecular mechanisms underlying these metabolic changes remain incompletely understood. Although NUAK1 and NUAK2, members of the NUAK kinase family have been implicated in CRC tumorigenesis, their specific roles in metabolic reprogramming that drives CRC progression and metastasis have not been elucidated. In this study, we demonstrate that NUAK1 and NUAK2 are overexpressed in human CRC tissues and that their expression is associated with increased tumor metastasis and poorer patient survival. NUAK1/2 promotes CRC cell proliferation and migration, whereas their depletion markedly reduces cell growth and migratory capacity. Furthermore, knockout of NUAK1/2 disrupts key metabolic pathways, including aerobic glycolysis, pentose phosphate pathway (PPP), and glutamine metabolism. Mechanistically, NUAK1/2 facilitates mTOR-driven metabolic reprogramming and promotes CRC growth and migration by suppressing AMPK activity. Depletion of NUAK1/2 impairs metabolic function, cellular growth, and migration potential in CRC cells, effects that are further enhanced by pharmacological activation of AMPK with AICAR and inhibition of mTOR using Rapamycin. In conclusion, these findings identify NUAK1/2 as critical regulators of CRC progression and migration through AMPK/mTOR-mediated metabolic reprogramming, highlighting their potential as therapeutic targets in colorectal cancer.