PO.TB03.01 · 肿瘤生物学
抑制GLUT3通过TEAD-VASP-Actin轴调节细胞力学，降低三阴性乳腺癌细胞的转移潜能
GLUT3 inhibition reduces metastatic potential of triple-negative breast cancer cells by modulating cell mechanics via the TEAD-VASP-Actin axis
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摘要 Abstract
中文摘要
三阴性乳腺癌（TNBC）是一种侵袭性乳腺癌亚型，缺乏激素（雌激素和孕激素）受体以及人表皮生长因子受体2（HER2），限制了靶向治疗的开发并导致患者预后不良。转移是TNBC死亡的主要因素，与癌细胞力学（如可变形性和收缩性）密切相关，然而调控这些力学特性的来自肿瘤微环境（TME）的分子信号线索仍知之甚少。
本研究探讨葡萄糖代谢，特别是葡萄糖转运蛋白3（GLUT3），在调节TNBC细胞力学和转移行为中的作用。GLUT3在GLUT亚型中具有最高的葡萄糖亲和力，在包括TNBC在内的多种癌症中上调，并与TNBC患者的不良预后和转移相关。我们证明，使用选择性抑制剂G3iA抑制GLUT3可使TNBC细胞的葡萄糖摄取、糖酵解和ATP产生减少30%，导致AMP激活的蛋白激酶（AMPK）激活和肌球蛋白活性抑制。肌球蛋白活性降低减少了细胞收缩性，最终减少细胞侵袭。AMPK激活还增加了YAP磷酸化，导致YAP靶基因表达降低。
我们还发现VASP，一种肌动蛋白丝成核因子和聚合酶，是一个受葡萄糖-AMPK信号轴调控的新型YAP-TEAD靶基因。此外，抑制GLUT3触发cAMP-蛋白激酶A（PKA）通路，该通路通过血管舒张剂刺激磷蛋白（VASP）损害肌动蛋白聚合。F-actin水平的降低与细胞硬度的降低相关，后者通过原子力显微镜测量。使用激活AMPK信号或cAMP-PKA信号通路的药理学抑制剂，我们表明这些改变的细胞力学——细胞硬度和收缩性——在体外减弱了细胞运动性。此外，我们证实了我们的发现，即GLUT3缺失的TNBC细胞在体内表现出肺转移减少。
总之，我们描绘了将细胞外葡萄糖信号转化为通过肌动蛋白重排调控细胞力学和运动性的分子通路。对于肌动蛋白重排，我们发现转录水平和翻译后修饰对VASP的调控至关重要。我们的发现揭示了葡萄糖代谢与癌细胞力学之间一种新的机制联系，并提供了详细的分子机制，为减轻TNBC转移提供了有前景的治疗途径。
查看英文原文 English abstract
Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype lacking hormone (estrogen and progesterone) receptors and human epidermal growth factor receptor 2 (HER2), limiting the development of targeted therapies and contributing to poor patient outcomes. Metastasis, a major contributor to TNBC mortality, is closely linked to cancer cell mechanics-such as deformability and contractility-yet the molecular signaling cues from the tumor microenvironment (TME) that regulate these mechanical properties remain poorly understood.
This study investigates the role of glucose metabolism, particularly the role of glucose transporter 3 (GLUT3), in modulating TNBC cell mechanics and metastatic behavior. GLUT3, which has the highest glucose affinity among GLUT isoforms, is upregulated in various cancers including TNBC and is associated with poor prognosis and metastasis in TNBC patients. We demonstrate that GLUT3 inhibition by a selective inhibitor G3iA reduces glucose uptake, glycolysis and ATP production by 30% in TNBC cells, leading to AMP-activated protein kinase (AMPK) activation and suppression of myosin activity. The decreased myosin activity reduces cell contractility and ultimately cell invasion. AMPK activation also increased YAP phosphorylation resulting decreased YAP target gene expressions.
We also identified VASP, an actin filament nucleator and polymerase, is a novel YAP-TEAD target gene that regulated by the glucose-AMPK signaling axis. Additionally, GLUT3 inhibition triggers the cAMP-Protein Kinase A (PKA) pathway, which impairs actin polymerization through vasodilator-stimulated phosphoprotein (VASP). The decreased F-actin levels correlates with reduced cell stiffness, which was measured by Atomic Force Microscope. Using pharmacological inhibitors that activate the AMPK signaling or the cAMP-PKA signaling pathways, we show that these altered cell mechanics-cell stiffness and contractility-diminishes cell motility in vitro. Furthermore, we confirmed our findings that GLUT3 null TNBC cells show reduced lung metastasis in vivo .
In summary, we delineate molecular pathways that translate extracellular glucose signaling into regulation of cell mechanics and motility via actin rearrangement. For the actin rearrangement, we discovered that regulation of VASP in transcriptional level and post-translational modification is critical. Our findings reveal a novel mechanistic link between glucose metabolism and cancer cell mechanics with detailed molecular mechanisms, offering a promising therapeutic avenue for mitigating TNBC metastasis.
利益披露 Disclosure
S. Oh, None..
W. Lee, None..
S. Kim, None..
J. Choe, None..
T. Kim, None.