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Lactate Oxidase Disrupts Lactate-Activated RAS and PI3K Oncogenic Signaling.
Chandler R Keller1, Steve R Martinez2,3,4, Alexys Keltz1,5
1Department of Translational Medicine and Physiology, Elson S. Floyd College of Medicine, Washington State University, Spokane, WA 99202, USA.
Cancers
|August 29, 2024
Summary
Lysyl oxidase (LOX) inhibits breast cancer by disrupting the hydroxycarboxylic acid receptor 1 (HCAR1) signaling complex. This mechanism, distinct from previous understanding, targets key oncogenic pathways for potential therapeutic strategies.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Lysyl oxidase (LOX) inhibits cancer cell proliferation and tumor growth.
- Previous mechanisms focused on LOX depleting tumor microenvironment (TME) lactate and producing H2O2.
Purpose of the Study:
- To elucidate the novel mechanism by which LOX inhibits breast cancer (BCa) progression.
- To investigate the role of hydroxycarboxylic acid receptor 1 (HCAR1) in lactate-mediated oncogenic signaling.
Main Methods:
- Investigated the assembly of the HCAR1-associated protein complex in BCa cells.
- Assessed the impact of LOX treatment on protein complex levels and lactate transporters (MCT1, MCT4).
- Analyzed the activation of RAS and PI3K signaling pathways.
Main Results:
- TME lactate triggers HCAR1 complex assembly (GRB2, SOS1, KRAS, GAB1, PI3K) activating RAS and PI3K pathways.
- LOX treatment reduced protein complex levels via proteasomal degradation.
- LOX inhibited lactate-stimulated MCT1 and MCT4 expression.
Conclusions:
- HCAR1 activation by lactate is critical for RAS/PI3K signaling nexus assembly and function in BCa.
- Disrupting this lactate signaling nexus via HCAR1 inhibition is detrimental to cancer cells.
- HCAR1 is a potential therapeutic target for controlling BCa progression.
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