Figure 1.

PI3K/AKT, YAP/TAZ, and PFK1/F-1,6-BP create a “Gordian Knot”, supporting cancer progression. In cancer cells, F-1,6-BP promotes glycolysis and activates ACLY, reducing citrate levels (which could inhibit PFK1 and PFK2) and increasing cytosolic acetyl-CoA (promoting lipid synthesis, protein and histone acetylation, and mevalonate pathway) and oxalacetate (OAA, sustaining nucleotide synthesis). Also, F-1,6-BP activates PI3K/AKT through Ras induction. PI3K/AKT can be also activated by tensile stresses from stress receptors. Once activated, PI3K/AKT promote transcription of glycolytic genes (though mTOR and low active PKM2), β-catenin stabilization (through PKM2, also promoted by ACLY), activation of glycolytic enzymes (favoring glycolysis), and YAP/TAZ activation (also induced by mevalonate pathway and β-catenin). Once translocated in the nucleus, YAP/TAZ mediate the transcription of genes promoting cell cycle progression and glycolysis. In parallel, (i) F-1,6-BP and AKT inhibit OXPHOS, thus increasing lactate production, which in turn inhibits the immune response and promotes extracellular acidification and drug resistance, and (ii) EMT is promoted by β-catenin and YAP/TAZ. Therapeutic strategies increasing citrate levels in cancer cells can inhibit glycolysis and F-1,6-BP production. Therefore, they may be useful to disrupt the Gordian Knot orchestrated by PI3K/AKT, YAP/TAZ, and PFK1/F-1,6-BP. Numbers (1–5) and uppercase letters (A–D) refer to regulatory mechanisms as described in Section 3 (numbers) and Section 4 (letters). Figure created with Biorender.