PI3K induces cytoskeletal reorganization, leading to release and activation of actin-bound aldolase.
Major finding: PI3K induces cytoskeletal reorganization, leading to release and activation of actin-bound aldolase.
Mechanism: PI3K activates RAC to remodel the actin cytoskeleton and coordinate glycolysis, independent of AKT.
Impact: PIK3CA mutations may result in excess free cytoplasmic aldolase that can drive tumor glycolysis.
The PI3K pathway is involved in the regulation of glucose metabolism and remodeling of the actin cytoskeleton, and alterations in PI3K signaling occur frequently in epithelial cancers. However, the coordination of these two processes by PI3K is not fully understood. Hu and colleagues found that PI3K inhibitors resulted in decreased glycolytic capacity in mammary epithelial cells, whereas AKT and mTOR inhibitors did not have this effect. Quantification of steady-state metabolite levels indicated that inhibition of PI3K, but not AKT, reduced the levels of the products of the aldolase reaction, indicating that PI3K regulates flux through the aldolase step of glycolysis. Further, aldolase activity increased with insulin stimulation of PI3K signaling or in response to activating PIK3CA mutations, due to the release of aldolase from actin filaments in the cytoskeleton into the cytoplasm following PI3K activation. The mobilization of aldolase from F-actin into the cytoplasm activates the enzymatic activity of aldolase and was mediated by PI3K activation of RAC. A RAC1 inhibitor prevented insulin-induced aldolase activity and mobilization, but not AKT phosphorylation. To test the effects of PI3K inhibition on glycolysis in cancer in vivo, a BRCA1-related breast cancer mouse model was used. In this model, PI3K inhibitors decreased the rate of conversion of 13C-pyruvate to 13C-lactate by 40%–50%, consistent with a reduction in mid- or lower glycolysis, independent of glucose uptake. In vivo isotope tracing analyses confirmed that PI3K inhibitors target the aldolase step of glycolysis, with the sharpest drop in 13C-glucose metabolites occurring in an aldolase product. Taken together, these data integrate the glycolytic and cytoskeletal roles of PI3K signaling, and show that PI3K-mediated activation of RAC leads to the release of active aldolase from the actin cytoskeleton independent of AKT, allowing for maximal glycolytic rate. These findings may be helpful in guiding the selection of PI3K versus AKT inhibitors for cancer treatment.
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