Lactate Oxidase Disrupts Lactate-Activated RAS and PI3K Oncogenic Signaling.

Simple Summary: The Aerococcus viridans bacterial lactate oxidase (LOX) is an enzyme absent in mammalian cells. LOX catalyzes lactate to pyruvate and hydrogen peroxide (H₂O₂), a function that was recently used for tumor microenvironment (TME) lactate removal and H₂O₂ production to induce cancer cell death. However, the functions of TME lactate other than being a metabolic intermediate or an energy source and the mechanism of LOX disruption of lactate-mediated cancer cell survival remain unknown. Our study aims at addressing these important cancer-related biological questions. We identified a novel onco-signaling nexus initiated by TME lactate activation of its cellular receptor hydroxycarboxylic acid receptor 1 (HCAR1) and amplified by HCAR-associated proteins that mediate the RAS and the PI3K pathways. This signaling model could explain many key survival strategies exerted by RAS, PI3K, and their effectors for cancer cell adaptation to TME changes, especially in the cells' use of lactate beyond an energy source. LOX was recently shown to inhibit cancer cell proliferation and tumor growth. The mechanism of this inhibition, however, has been exclusively attributed to LOX depletion of TME lactate, a cancer cell energy source, and production of H₂O₂, an oxidative stressor. We report that TME lactate triggers the assembly of the lactate receptor hydroxycarboxylic acid receptor 1 (HCAR1)-associated protein complex, which includes GRB2, SOS1, KRAS, GAB1, and PI3K, for the activation of both the RAS and the PI3K oncogenic signaling pathways in breast cancer (BCa) cells. LOX treatment decreased the levels of the proteins in the protein complex via induction of their proteasomal degradation. In addition, LOX inhibited lactate-stimulated expression of the lactate transporters MCT1 and MCT4. Our data suggest that HCAR1 activation by lactate is crucial for the assembly and function of the RAS and PI3K signaling nexus. Shutting down lactate signaling by disrupting this nexus could be detrimental to cancer cells. HCAR1 is therefore a promising target for the control of the RAS and the PI3K signaling required for BCa progression. Thus, our study provides insights into lactate signaling regulation of cancer progression and extends our understanding of LOX's functional mechanisms that are fundamental for exploring its therapeutic potential. [ABSTRACT FROM AUTHOR]