Lactate does not activate NF-κB in oxidative tumor cells

Area of Science:

• Oncometabolites
• Cancer Metabolism
• Tumor Microenvironment

Background:

• Lactate is an emerging oncometabolite with protumoral activities.
• Lactate promotes angiogenesis via HIF-1 and NF-κB activation.
• Lactate uptake and metabolism involve MCT1, LDH-1, and PHD inhibition.

Purpose of the Study:

• To investigate if exogenous lactate activates NF-κB in oxidative tumor cells.
• To understand the role of lactate metabolism in tumor cell signaling.

Main Methods:

• Utilized oxidative human tumor cell lines (HeLa, SiHa, Cal27, MCF7).
• Assessed NF-κB activation in response to exogenous lactate.
• Investigated NADH utilization pathways (OXPHOS vs. NAD(P)H oxidases).

Main Results:

• Oxidative tumor cells (HeLa, SiHa, Cal27, MCF7) did not activate NF-κB in response to lactate.
• Lactate-derived pyruvate inhibited PHDs, but NADH preferentially fueled mitochondrial oxidative phosphorylation (OXPHOS).
• The malate-aspartate shuttle was identified as crucial for oxidative lactate metabolism.

Conclusions:

• Oxidative tumor cells utilize lactate primarily as an oxidative fuel, not for NF-κB signaling.
• NADH generated from lactate metabolism supports OXPHOS in these cells.
• The malate-aspartate shuttle plays a key role in channeling lactate-derived metabolites to OXPHOS.