Figure 5.

Glycolysis-induced autophagy or mixed, mesenchymal/autophagic phenotype in the presence of glucose sufficiency. Stimuli, either tumor cell-autonomous or from the TME (extracellular) increase the expression and/or activity of one or more glycolytic components (transporters, enzymes or metabolites). At least one glycolytic component (HKII) has been shown to interact with mTOR and inhibit mTORC1. Inhibition of mTORC1 may also occur during mitotic arrest. This inhibition then leads to AMPK activation and autophagy induction. Prolonged mitotic arrest may also promote AMPK-driven upregulation of glycolysis which, through mechanisms similar to those described before (e.g., upregulation of HKII), may lead to AMPK activation and autophagy induction. When these events are induced in epithelial tumor cells, they give rise to an autophagic tumor cell. When they are induced in a tumor cell that has already acquired mesenchymal traits, then they are expected to give rise to a mixed, mesenchymal/autophagic phenotype. AMPK, adenosine monophosphate-activated protein kinase; ATP, adenosine triphosphate; EMT, epithelial–mesenchymal transition; HKII, hexokinase II; mTOR, mechanistic target of rapamycin; mTORC1, mTOR complex 1; TF, transcription factor.