title: MK2206 overcomes the resistance of human liver cancer stem cells to sorafenib by inhibition of pAkt and upregulation of pERK.
abstract: Sorafenib is a multikinase inhibitor for the treatment of hepatocellular carcinoma. However, most patients who initially respond to sorafenib become refractory. In a previous study, we demonstrated that sphere-forming cells derived from liver cancer cell lines possess the properties of liver cancer stem cells (LCSCs). In the present study, we found that successive passages of LCSCs were more resistant to sorafenib, and LCSCs treated with sorafenib showed an increase in spheroid formation with a lower inhibition rate. MK2206, but not various other inhibitors of cell signaling pathways, enhanced their sensitivity to sorafenib, increased the apoptotic rate, and suppressed the growth of LCSC xenografts in vivo (P < 0.01); sorafenib treatment decreased the level of active phosphorylated (p)Akt (Thr308) and reduced the levels of active pAkt (Ser473) and extracellular signal-regulated kinase (ERK) in LCSCs, whereas MK2206 reduced pAkt expression and increased pERK expression. Cotreatment with sorafenib and MK2206 reduced pAkt and pERK expression in LCSCs and xenografted tumors (P < 0.01). Treatment with either sorafenib or MK2206 decreased the expression of EpCAM and CD133 in LCSCs, which was more evident after combined treatment. Based on these results, we conclude that resistance to sorafenib is associated with weak ERK signaling and strong Akt signaling in LCSCs. By inhibition of Akt and upregulation of ERK, MK2206 overcomes the resistance of LCSCs to sorafenib.
authors.affiliation: Molecular Oncology Laboratory, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Beibei
authors.initials: B
authors.lastname: Zhai
authors.affiliation: Molecular Oncology Laboratory, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Molecular Oncology Laboratory, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Sun
authors.affiliation: Molecular Oncology Laboratory, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Cao
authors.affiliation: Molecular Oncology Laboratory, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Linlin
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Molecular Oncology Laboratory, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Radioactive Intervention, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Naijian
authors.initials: N
authors.lastname: Ge
authors.affiliation: Molecular Oncology Laboratory, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Chen
authors.affiliation: Molecular Oncology Laboratory, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Haihua
authors.initials: H
authors.lastname: Qian
authors.affiliation: Molecular Oncology Laboratory, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China. yinzfk@aliyun.com.
authors.forename: Zhengfeng
authors.identifier: http://orcid.org/0000-0001-6203-9507
authors.initials: Z
authors.lastname: Yin
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000378:metabolism; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology*; D006801:Humans; D007124:Immunoenzyme Techniques; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000077157:Sorafenib; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D006575:Heterocyclic Compounds, 3-Ring; C548887:MK 2206; D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Hepatocellular carcinoma; Liver cancer stem cells; MK2206; Sorafenib