Gβγ mediates activation of Rho guanine nucleotide exchange factor ARHGEF17 that promotes metastatic lung cancer progression

Irving García-Jiménez,Rodolfo Daniel Cervantes-Villagrana,Jorge Eduardo Del-Río-Robles,Alejandro Castillo-Kauil,Yarely Mabell Beltrán-Navarro,Jonathan García-Román,Guadalupe Reyes-Cruz,José Vázquez-Prado

doi:10.1016/j.jbc.2021.101440

Abstract

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.

Highlights

Metastatic lung cancer is a major cause of death worldwide
Tumorigenic role of ARHGEF17, a Rho guanine nucleotide exchange factor (RhoGEF) that correlates with reduced survival of non–small cell lung carcinoma patients with high-grade tumors
Lungs with multiple metastatic tumors weighted more than normal lungs from healthy mice (Fig. 1H). Both the weight (Fig. 1H) and the number of lung macrometastasis (Fig. 1I) were significantly attenuated in mice inoculated with cells in which ARHGEF17 was knocked down in comparison to those inoculated with sh-Control cells

Summary

Introduction

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). Cellular assays 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. Lipid-derived agonists and chemokines within the tumor microenvironment attract stromal cells and promote dissemination of cancer cells [1,2,3] They stabilize the active conformation of chemotactic G protein–coupled receptors (GPCRs) to engage an intracellular repertoire of G protein– dependent and independent mechanisms [4, 5].

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Conclusion