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Biochem Biophys Res Commun. 2013 Apr 26;434(1):35-41. doi: 10.1016/j.bbrc.2013.03.070. Epub 2013 Mar 29.

The blockage of Ras/ERK pathway augments the sensitivity of SphK1 inhibitor SKI II in human hepatoma HepG2 cells.

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Department of Oncology, Institute of Medicinal Biotechnology, Peking Union Medical College, Chinese Academy of Medical Sciences, 1# Tiantan Xili, Beijing 100050, China.


The treatment of hepatocellular carcinoma (HCC) remains a challenge and the future of cancer therapy will incorporate rational combinations directed to molecular targets that cooperate to drive critical pro-survival signaling. Sphingosine kinase 1 (SphK1) has been shown to regulate various processes important for cancer progression. Given the up-regulated expression of SphK1 in response to the silence of N-ras and other interactions between Ras/ERK and SphK1, it was speculated that combined inhibition of Ras/ERK and SphK1 would create enhanced antitumor effects. Experimental results showed that dual blockage of N-ras/ERK and SphK1 resulted in enhanced growth inhibitions in human hepatoma cells. Similarly, MEK1/2 Inhibitor U0126 potentiated SKI II-induced apoptosis in hepatoma HepG2 cells, consistently with the further attenuation of Akt/ERK/NF-κB signaling pathway. It was also shown that the combination of SKI II and U0126 further attenuated the migration of hepatoma HepG2 cells via FAK/MLC-2 signaling pathway. Taken together, the dual inhibition of SphK1 and Ras/ERK pathway resulted in enhanced effects, which might be an effective therapeutic approach for the treatment of HCC.

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