Monensin synergizes with chemotherapy in uveal melanoma through suppressing RhoA.

OBJECTIVE: Uveal melanoma (UM) is the common primary cancer of the eye and new treatments are needed. Substantial evidence has shown that an antibiotic monensin is an attractive candidate for the development of anti-cancer drug. In this study, we investigated the potential of repositioning monensin for the treatment of UM in the pre-clinical setting. MATERIALS AND METHODS: Cellular activity assays were performed using multiple cell lines representing UM models with different cellular origins and genetic profiling and normal cells as control. Combination studies were performed using Chou-Talalay method. Mechanism studies were performed using immunoblotting and ELISA. RESULTS: Monensin was effective against all tested UM cell lines and less effective against normal fibroblast cells. Monensin induced G0/G1 arrest and thus decreased S phase, leading to UM cell growth inhibition. It also inhibited migration and induced apoptosis in UM cells. In addition, the combination of monensin and dacarbazine was synergistic in targeting UM cells. Our mechanistic studies showed that monensin specifically decreased activity of RhoA without affecting other small GTPases, such as Ras and Rac1. Consistently, monensin decreased phosphorylation of downstream effectors of RhoA signaling, including ROCK, MYPT1 and MLC. Rescue studies using RhoA activator calpeptin showed that calpeptin significantly abolished the inhibitory effects of monensin on RhoA activity, proliferation, migration and survival, confirming that RhoA is the target of monensin in UM cells. CONCLUSIONS: Our study demonstrates that monensin is a potent inhibitor of UM and synergizes with chemotherapy, via suppressing RhoA activity and RhoA-mediated signaling. Our findings suggest that monensin may be a potential lead compound for further development into a drug for UM treatment.

Copyright Governance for Online Short Videos: Perspective of Transaction Cost Economics.

In recent years, copyright governance for short videos has become a hot issue of common concern in the academic community and the industry. Therefore, this study intends to explore the economic aspect of copyright governance in relation to the proliferation of infringing short videos. The short video industry of China has been taken as a case to demonstrate the copyright governance issue. Transaction cost theory has been applied to analyze the economic aspect of copyright governance in terms of four dimensions: bounded rationality, opportunism, environmental uncertainty, and asset specificity. From the perspective of transaction cost economics, the problem of short video infringement is observed to be essentially a market failure due to high transaction costs. In the short video market, substantial transaction costs are incurred in the legal transaction of copyright with these costs considered to be too high. This is especially the case when transaction costs exceed the net proceeds initially expected by short video users from the authorization, making it impossible to carry out the transaction and leading to infringement. To effectively control the copyright infringement of short videos, it is necessary to build a cross-platform information-sharing mechanism to reduce search costs, establish a unified copyright management platform to reduce coordination costs, and give full attention to the role of technical support to reduce regulatory costs.