Keller Chandler R, Martinez Steve R, Keltz Alexys, Chen Michelle, Li Weimin
Department of Translational Medicine and Physiology, Elson S. Floyd College of Medicine, Washington State University, Spokane, WA 99202, USA.
Department of Surgery, The Everett Clinic, Part of Optum, Everett, WA 98201, USA.
Cancers (Basel). 2024 Aug 10;16(16):2817. doi: 10.3390/cancers16162817.
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 HO, 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.
最近研究表明，赖氨酰氧化酶（LOX）可抑制癌细胞增殖和肿瘤生长。然而，这种抑制机制完全归因于LOX消耗了肿瘤微环境（TME）中的乳酸（一种癌细胞能量来源）以及产生了氧化应激源羟基自由基（HO）。我们报告称，TME乳酸触发了乳酸受体羟基羧酸受体1（HCAR1）相关蛋白复合物的组装，该复合物包括生长因子受体结合蛋白2（GRB2）、七号染色体上的鸟嘌呤核苷酸交换因子1（SOS1）、Kirsten大鼠肉瘤病毒癌基因（KRAS）、GRB2相关结合蛋白1（GAB1）和磷脂酰肌醇-3激酶（PI3K），从而激活乳腺癌（BCa）细胞中的RAS和PI3K致癌信号通路。LOX处理通过诱导蛋白复合物中蛋白质的蛋白酶体降解，降低了这些蛋白质的水平。此外，LOX抑制了乳酸刺激的乳酸转运蛋白单羧酸转运蛋白1（MCT1）和单羧酸转运蛋白4（MCT4）的表达。我们的数据表明，乳酸对HCAR1的激活对于RAS和PI3K信号枢纽的组装和功能至关重要。通过破坏这种信号枢纽来关闭乳酸信号可能对癌细胞有害。因此，HCAR1是控制BCa进展所需的RAS和PI3K信号传导的一个有前景的靶点。因此，我们的研究为癌症进展的乳酸信号调节提供了见解，并扩展了我们对LOX功能机制的理解，这对于探索其治疗潜力至关重要。
