Synergistic induction of cancer cell migration regulated by Gβγ and phosphatidylinositol 3-kinase

Abstract

Phosphatidylinositol 3-kinase (PI3K) is essential for both G protein-coupled receptor (GPCR)- and receptor tyrosine kinase (RTK)-mediated cancer cell migration. Here, we have shown that maximum migration is achieved by full activation of phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 1 (P-Rex1) in the presence of Gβγ and PI3K signaling pathways. Lysophosphatidic acid (LPA)-induced migration was higher than that of epidermal growth factor (EGF)-induced migration; however, LPA-induced activation of Akt was lower than that stimulated by EGF. LPA-induced migration was partially blocked by either Gβγ or RTK inhibitor and completely blocked by both inhibitors. LPA-induced migration was synergistically increased in the presence of EGF and vice versa. In correlation with these results, sphingosine-1-phosphate (S1P)-induced migration was also synergistically induced in the presence of insulin-like growth factor-1 (IGF-1). Finally, silencing of P-Rex1 abolished the synergism in migration as well as in Rac activation. Moreover, synergistic activation of MMP-2 and cancer cell invasion was attenuated by silencing of P-Rex1. Given these results, we suggest that P-Rex1 requires both Gβγ and PI3K signaling pathways for synergistic activation of Rac, thereby inducing maximum cancer cell migration and invasion.

Reactive Oxygen Species Mediates Lysophosphatidic Acid-induced Migration of SKOV-3 Ovarian Cancer Cells

“…is possible that G protein-coupled LPA receptor evokes activation of PI3K and release of Gβγ subunit and leads to the activation of P-Rex1. In line with this, it has been reported that LPA induces cancer cell migration through the activation of P-Rex1 [15].…”

“…Plethora of reports suggests that LPA mainly activates three MAPK signaling pathways including the Ras/MEKK/ MAPK, p38 MAPK, and JNK pathways [2,21]. In addition to these MAPK signaling pathways, it also has been reported that LPA stimulates PI3K signaling pathways and regulates variety of physiological responses such as DNA synthesis and cell motility [15,17]. Although the mechanism underlying activation of PI3K is still unclear, inhibition of PI3K…”

“…In addition, LPA modulates migration of cancer cells such as ovarian cancer cells and rat hepatoma cells [8,14]. Recently, it also has been reported that LPA synergistically induces cancer cell migration in the presence of growth factors [15].…”

Statins Perturb Gβγ Signaling and Cell Behavior in a Gγ Subtype Dependent Manner

“…Cell migration and invasion play a critical role in cancer cell progression and subsequent cancer metastasis (Kirui et al, 2010). The role of Gbg signaling in cell migration and invasion is thoroughly investigated and well documented (Kirui et al, 2010;Tang et al, 2011;Kim et al, 2012;Vázquez-Prado et al, 2016). In addition to PI3K, Gbg signaling contributes to full activation of PIP3-dependent Rac exchanger 1 (P-Rex1) and thus to Rac1-mediated cell mobility (Dbouk et al, 2012;Kim et al, 2012).…”

Structural and Biochemical Characterization of the Catalytic Core of the Metastatic Factor P-Rex1 and Its Regulation by PtdIns(3,4,5)P3

“…Thus, small molecules that can inhibit enzymes responsible for cell migration represent an intriguing new direction for cancer chemotherapy. Phosphatidylinositol 3,4,5-trisphosphate (PIP 3 )-dependent Rac exchanger (P-Rex) 1 and P-Rex2 are increasingly recognized for their role in the metastasis of breast cancer, prostate cancer, and melanoma (Berger et al, 2012; Lindsay et al, 2011; Qin et al, 2009; Sosa et al, 2010), and it has been shown that P-Rex enzymes can drive migratory and invasive phenotypes in laboratory cell lines (Campbell et al, 2013; Kim et al, 2012). Therefore, P-Rex1 and P-Rex2 represent attractive therapeutic targets in cancers where P-Rex overexpression is responsible for clinical progression.…”