title: The blockage of Ras/ERK pathway augments the sensitivity of SphK1 inhibitor SKI II in human hepatoma HepG2 cells.
abstract: 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.
authors.affiliation: Department of Oncology, Institute of Medicinal Biotechnology, Peking Union Medical College, Chinese Academy of Medical Sciences, 1# Tiantan Xili, Beijing 100050, China.
authors.forename: Caixia
authors.initials: C
authors.lastname: Zhang
authors.forename: Hongwei
authors.initials: H
authors.lastname: He
authors.forename: Hao
authors.initials: H
authors.lastname: Zhang
authors.forename: Dongke
authors.initials: D
authors.lastname: Yu
authors.forename: Wuli
authors.initials: W
authors.lastname: Zhao
authors.forename: Yi
authors.initials: Y
authors.lastname: Chen
authors.forename: Rongguang
authors.initials: R
authors.lastname: Shao
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D004357:Drug Synergism; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors*; D013844:Thiazoles / Q000008:administration & dosage*; D018631:ras Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D000099157:Sphingosine Kinase
chemical_list: D017853:Phosphotransferases (Alcohol Group Acceptor); D013844:Thiazoles; D018631:ras Proteins; D000099157:Sphingosine Kinase; C525025:4-(4-(4-chloro-phenyl)thiazol-2-ylamino)phenol