Metastatic lung cancer is a major cause of death worldwide. Dissemination of cancer cells can be facilitated by various agonists within the tumor microenvironment, including by lysophosphatidic acid (LPA). We postulate that Rho guanine nucleotide exchange factors (RhoGEFs), which integrate signaling cues driving cell migration, are critical effectors in metastatic cancer. Specifically, we addressed the hypothetical role of ARHGEF17, a RhoGEF, as a potential effector of Gβγ in metastatic lung cancer cells responding to LPA. Here, we show that ARHGEF17, originally identified as a tumor endothelial marker, is involved in tumor growth and metastatic dissemination of lung cancer cells in an immunocompetent murine model. Gene expression-based analysis of lung cancer datasets showed that increased levels of ARHGEF17 correlated with reduced survival of patients with advanced-stage tumors. Cellular assays also revealed that this RhoGEF participates in the invasive and migratory responses elicited by Gi protein-coupled LPA receptors via the Gβγ subunit complex. We demonstrate that this signaling heterodimer promoted ARHGEF17 recruitment to the cell periphery and actin fibers. Moreover, Gβγ allosterically activates ARHGEF17 by the removal of inhibitory intramolecular restrictions. Taken together, our results indicate that ARHGEF17 may be a valid potential target in the treatment of metastatic lung cancer.

中文翻译：

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Gβγ 介导 Rho 鸟嘌呤核苷酸交换因子 ARHGEF17 的激活，从而促进转移性肺癌的进展。

转移性肺癌是全世界死亡的主要原因。肿瘤微环境中的各种激动剂可以促进癌细胞的传播，包括溶血磷脂酸 (LPA)。我们假设整合信号线索驱动细胞迁移的 Rho 鸟嘌呤核苷酸交换因子 (RhoGEFs) 是转移性癌症的关键效应物。具体来说，我们讨论了 ARHGEF17（一种 RhoGEF）作为 Gβγ 在对 LPA 有反应的转移性肺癌细胞中的潜在效应物的假设作用。在这里，我们展示了 ARHGEF17，最初被确定为肿瘤内皮标志物，在免疫活性小鼠模型中参与了肺癌细胞的肿瘤生长和转移性传播。肺癌数据集的基于基因表达的分析表明，ARHGEF17 水平升高与晚期肿瘤患者的生存率降低相关。细胞分析还显示，这种 RhoGEF 参与了由 Gi 蛋白偶联的 LPA 受体通过 Gβγ 亚基复合物引发的侵袭和迁移反应。我们证明了这种信号异二聚体促进了 ARHGEF17 向细胞外围和肌动蛋白纤维的募集。此外，Gβγ 通过消除抑制性分子内限制来变构激活 ARHGEF17。总之，我们的结果表明 ARHGEF17 可能是治疗转移性肺癌的有效潜在靶点。细胞分析还显示，这种 RhoGEF 参与了由 Gi 蛋白偶联的 LPA 受体通过 Gβγ 亚基复合物引发的侵袭和迁移反应。我们证明了这种信号异二聚体促进了 ARHGEF17 向细胞外围和肌动蛋白纤维的募集。此外，Gβγ 通过消除抑制性分子内限制来变构激活 ARHGEF17。总之，我们的结果表明 ARHGEF17 可能是治疗转移性肺癌的有效潜在靶点。细胞分析还显示，这种 RhoGEF 参与了由 Gi 蛋白偶联的 LPA 受体通过 Gβγ 亚基复合物引发的侵袭和迁移反应。我们证明了这种信号异二聚体促进了 ARHGEF17 向细胞外围和肌动蛋白纤维的募集。此外，Gβγ 通过消除抑制性分子内限制来变构激活 ARHGEF17。总之，我们的结果表明 ARHGEF17 可能是治疗转移性肺癌的有效潜在靶点。