Involvement of Ras GTPase-activating protein SH3 domain-binding protein 1 in the epithelial-to-mesenchymal transition-induced metastasis of breast cancer cells via the Smad signaling pathway

Abstract

In situ models of epithelial-to-mesenchymal transition (EMT)-induced carcinoma develop into metastatic carcinoma, which is associated with drug resistance and disease recurrence in human breast cancer. Ras GTPase-activating protein SH3 domain-binding protein 1 (G3BP1), an essential Ras mediator, has been implicated in cancer development, including cell growth, motility, invasion and apoptosis. Here, we demonstrated that the upregulation of G3BP1 activates the EMT in breast cancer cells. Silencing Smads almost completely blocked this G3BP1-induced EMT, suggesting that this process depends on the Smad signaling pathway. We also found that G3BP1 interacted with the Smad complex. Based on these results, we proposed that G3BP1 might act as a novel co-factor of Smads by regulating their phosphorylation status. Moreover, knockdown of G3BP1 suppressed the mesenchymal phenotype of MDA-MB-231 cells in vitro and suppressed tumor growth and lung metastasis of 4T1 cells in vivo. Our findings identified a novel function of G3BP1 in the progression of breast cancer via activation of the EMT, indicating that G3BP1 might represent a potential therapeutic target for metastatic human breast cancer.

Rasputin a decade on and more promiscuous than ever? A review of G3BPs

“…Instead, emerging evidence suggests that these proteins may mediate alterations in gene expression at various levels of control, in response to a range of cell signals, in various cellular and sub-cellular contexts. For example, G3BPs form SGs [14], possess antiviral activities [34] and have a role in epithelial-to-mesenchymal transition (EMT)-induced metastasis [35,36]. The emerging roles of G3BPs in SGs formation, cancer metastasis and viral infection, has driven extensive research to explore the role of G3BPs in different cellular contexts.…”

“…Likewise, G3BP1 knockdown blocked the mesenchymal phenotype of MDA-MB-231 cells in vitro and repressed tumour growth and metastasis in 4T1 cells in vivo, demonstrating that G3BP1 has a role in breast cancer progression and may serve as a potential therapeutic target for metastatic human breast cancer. G3BP1 plays an essential role in the activation of Smads through phosphorylation which in turn stimulate EMT factors [36]. Furthermore, G3BP1 is overexpressed in hepatocellular carcinoma (HCC) and is involved in EMT of HCC by stimulating the expression of Slug, a member of the SNAIL family of zinc finger transcription factors which induces EMT.…”

A GTPase-activating protein–binding protein (G3BP1)/antiviral protein relay conveys arteriosclerotic Wnt signals in aortic smooth muscle cells

“…Recent data have demonstrated that Arg methylation of G3BP1 inhibits RNA binding and stress granule formation (67). However, G3BP1 has roles beyond RNA stress granule formation, including regulation of c-Myc RNA turnover (68), inhibition of miR-1 biogenesis (69), intron splicing (70), and signal transduction (23,71,72).…”

SPHK1 (sphingosine kinase 1) induces epithelial-mesenchymal transition by promoting the autophagy-linked lysosomal degradation of CDH1/E-cadherin in hepatoma cells

“…The epithelial-mesenchymal transition (EMT) enables polarized epithelial cells to undergo multiple biochemical changes to exhibit characteristics of mesenchymal cell phenotypes, including enhanced migration and invasion capacities 8 . The EMT converts benign tumors into invasive, metastatic tumors and plays a critical role in the regulation of tumor progression and metastasis 9 .…”