Lactate jump-starts mTORC1 in cancer cells

Abstract

The kinase mammalian target of rapamycin (mTOR) is a major regulatory hub that senses and integrates nutrient, energy, and growth factor inputs to promote cell growth. In this issue of EMBO Reports, Byun et al [1] report that high intracellular levels of lactate activate mTORC1 in KRAS transformed cells independently of a growth factor input. This suggests a mechanism for how mTORC1 can be co‐opted to support oncogenic growth and proliferation.

Figure 1. High intracellular levels of lactate activate mTORC1 by relieving TSC repression of Rheb

Left panel: Under normal physiological conditions, mTORC1 is tightly regulated. mTORC1 is activated by Rheb. Rheb itself is negatively regulated by TSC. TSC is in turn repressed by intracellular cues that sense when conditions are favorable for cell growth. Right panel: Highly glycolytic conditions generate large amounts of lactate. When intracellular lactate levels exceed a certain threshold, it prevents TSC from interacting with Rheb leading to constitutive mTORC1 activity.