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Nutrition deprivation (ND) is a common feature of the tumor microenvironment. Tumor cells, therefore, frequently develop resistance mechanisms against ND. One of these mechanisms is the activation of the AMP-activated protein kinase (AMPK), which promotes cell survival under ND. AMPK activation promotes the activity of eukaryotic elongation factor 2 kinase (eEF2K), thereby blocking protein synthesis. The results of the present study indicated the inhibiting effect of AMPK activation on mitogen-activated protein kinase (ERK1/2) activity, which in turn downregulates G1/S transition and promotes cell survival by mediating eEF2K under ND. The knockdown of ERK1/2 enhances cancer cell survival under ND. In the presence of nutrients, eEF2k interacts with dual-specificity mitogen-activated protein kinase kinase (MEK)1/2, conferring a positive feedback loop via MEK1/2-ERK1/2-ribosomal protein S6 kinase α-1-eEF2K signaling, leading to the constitutive activation of ERK1/2. By contrast, under acute ND, AMPK activation blocked the interaction between eEF2K and MEK1/2, contributing to the increased resistance of cancer cells to ND. The present findings reveal a previously undiscovered mechanism that uses AMPK activation to mediate ERK1/2-regulated protein synthesis and cell survival by inhibiting eEF2K-MEK1/2 interaction under ND conditions.

AMPK decreases ERK1/2 activity and cancer cell sensitivity to nutrition deprivation by mediating a positive feedback loop involving eEF2K