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.
近期研究表明，赖氨酰氧化酶（LOX）能够抑制癌细胞增殖与肿瘤生长。然而，该抑制机制此前仅被归因于LOX消耗肿瘤微环境中的乳酸（癌细胞的能量来源）并产生过氧化氢（一种氧化应激因子）。本研究发现，在乳腺癌细胞中，肿瘤微环境中的乳酸会触发乳酸受体羟基羧酸受体1（HCAR1）相关蛋白复合物的组装，该复合物包含GRB2、SOS1、KRAS、GAB1和PI3K，进而激活RAS和PI3K致癌信号通路。LOX处理通过诱导这些蛋白的蛋白酶体降解，降低了该蛋白复合物中各成分的表达水平。此外，LOX还能抑制乳酸刺激的乳酸转运蛋白MCT1和MCT4的表达。我们的数据表明，乳酸激活HCAR1对于RAS和PI3K信号枢纽的组装与功能至关重要。通过破坏该信号枢纽来阻断乳酸信号传导可能对癌细胞产生抑制作用。因此，HCAR1是控制乳腺癌进展所必需的RAS和PI3K信号通路的一个潜在治疗靶点。本研究揭示了乳酸信号对癌症进展的调控机制，拓展了对LOX功能机制的理解，这为探索其治疗潜力奠定了重要基础。
Lactate Oxidase Disrupts Lactate-Activated RAS and PI3K Oncogenic Signaling
肿瘤(癌症)患者之家