Rhosin Suppressed Tumor Cell Metastasis through Inhibition of Rho/YAP Pathway and Expression of RHAMM and CXCR4 in Melanoma and Breast Cancer Cells

Abstract

The high mortality rate of cancer is strongly correlated with the development of distant metastases at secondary sites. Although Rho GTPases, such as RhoA, RhoB, RhoC, and RhoE, promote tumor metastasis, the main roles of Rho GTPases remain unidentified. It is also unclear whether rhosin, a Rho inhibitor, acts by suppressing metastasis by a downstream inhibition of Rho. In this study, we investigated this mechanism of metastasis in highly metastatic melanoma and breast cancer cells, and the mechanism of inhibition of metastasis by rhosin. We found that rhosin suppressed the RhoA and RhoC activation, the nuclear localization of YAP, but did not affect ERK1/2, Akt, or NF-κB activation in the highly metastatic cell lines B16BL6 and 4T1. High expression of YAP was associated with poor overall and recurrence-free survival in patients with breast cancer or melanoma. Treatment with rhosin inhibited lung metastasis in vivo. Moreover, rhosin inhibited tumor cell adhesion to the extracellular matrix via suppression of RHAMM expression, and inhibited SDF-1-induced cell migration and invasion by decreasing CXCR4 expression in B16BL6 and 4T1 cells. These results suggest that the inhibition of RhoA/C-YAP pathway by rhosin could be an extremely useful therapeutic approach in patients with melanoma and breast cancer.

Image quantification technique reveals novel lung cancer cytoskeletal phenotype with partial EMT signature

“…. When we inhibited this pathway with Rhosin 42 , it resulted in a complete suspension of stress fiber formation in the drug treated cells (Fig.4B). To quantify the suspension of stress fiber formation, we compared the number of extracted fibers as well as the total length of fiber extracted in untreated cells vs inhibitor treated cells (Fig.4E, Supplementary Fig.…”

“…First, we inhibited the Rho-ROCK pathway, which is one of the most well-known EMT pathways 36,37,38.39,40,41 . When we inhibited this pathway with Rhosin 42 , it resulted in a complete suspension of stress fiber formation in the drug treated cells (Fig. 4B).…”

Application and Study of ROCK Inhibitors in Pulmonary Fibrosis: Recent Developments and Future Perspectives

“…Importantly, ROCK inhibitors inhibited the proliferation and activation of fibroblasts and myofibroblasts mediated by the YAP/TAZ signaling pathway . In studies performed in vitro, knocking down RhoA attenuated YAP/TAZ nuclear translocation and enhanced cytoplasmic YAP expression, which resulted in the inhibition of cell adhesion, migration, invasion, and metastasis . Remarkably, crosstalk between the cellular polarization machinery is directed by active ROCK and YAP activation after their nuclear localization .…”

“…81 In studies performed in vitro, knocking down RhoA attenuated YAP/TAZ nuclear translocation and enhanced cytoplasmic YAP expression, which resulted in the inhibition of cell adhesion, migration, invasion, and metastasis. 82 Remarkably, crosstalk between the cellular polarization machinery is directed by active ROCK and YAP activation after their nuclear localization. 83 Although the above findings suggest that Rho/ROCK may be an important regulator in the YAP/TAZ/TEAD signaling pathway that mediates certain profibrosis-promoting target genes, the molecular mechanism by which ROCK controls YAP phosphorylation is unclear (Figure 3B).…”

PI3K/Akt/YAP signaling promotes migration and invasion of DLD‑1 colorectal cancer cells

“…In mammalian systems, YAP translocates from the cytoplasm to the nucleus, where it induces the transcriptional activity of genes associated with cell proliferation, apoptosis, migration, and invasion by interacting with DNA-binding transcription factors (8,9). Accumulating evidence suggests that YAP contributes to the progression in human cancers, including breast cancer, melanoma, and lung cancer (10)(11)(12). Aberrant YAP expression or activation is also associated with poor prognosis (13)(14)(15).…”