title: CHK1 targets spleen tyrosine kinase (L) for proteolysis in hepatocellular carcinoma.
abstract: Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies resistant to current chemotherapies or radiotherapies, which makes it urgent to identify new therapeutic targets for HCC. In this study, we found that checkpoint kinase 1 (CHK1) was frequently overexpressed and correlated with poor clinical outcome in patients with HCC. We further showed that the CHK1 inhibitor GÖ6976 was capable of sensitizing HCC cells to cisplatin, indicating that CHK1 may have oncogenic function in HCC. We found that CHK1 phosphorylated the tumor suppressor spleen tyrosine kinase (L) (SYK[L]) and identified the phosphorylation site at Ser295. Furthermore, CHK1 phosphorylation of SYK(L) promoted its subsequent proteasomal degradation. Expression of a nonphosphorylated mutant of SYK(L) was more efficient at suppressing proliferation, colony formation, mobility, and tumor growth in HCC lines. Importantly, a strong inverse correlation between the expression levels of CHK1 and SYK(L) was observed in patients with HCC. Collectively, our data demonstrate that SYK(L) is a substrate of CHK1 in tumor cells and suggest that targeting the CHK1/SYK(L) pathway may be a promising strategy for treating HCC.
authors.affiliation: State Key Laboratory of Oncology in South China.
authors.forename: Jian
authors.initials: J
authors.lastname: Hong
authors.forename: Kaishun
authors.initials: K
authors.lastname: Hu
authors.forename: Yunfei
authors.initials: Y
authors.lastname: Yuan
authors.forename: Yi
authors.initials: Y
authors.lastname: Sang
authors.forename: Qiangui
authors.initials: Q
authors.lastname: Bu
authors.forename: Guihua
authors.initials: G
authors.lastname: Chen
authors.forename: Longjun
authors.initials: L
authors.lastname: Yang
authors.forename: Binkui
authors.initials: B
authors.lastname: Li
authors.forename: Pinzhu
authors.initials: P
authors.lastname: Huang
authors.forename: Dongtai
authors.initials: D
authors.lastname: Chen
authors.forename: Yi
authors.initials: Y
authors.lastname: Liang
authors.forename: Ruhua
authors.initials: R
authors.lastname: Zhang
authors.forename: Jingxuan
authors.initials: J
authors.lastname: Pan
authors.forename: Yi-Xin
authors.initials: YX
authors.lastname: Zeng
authors.forename: Tiebang
authors.initials: T
authors.lastname: Kang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002227:Carbazoles / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D000071877:Checkpoint Kinase 1; D002945:Cisplatin / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008113:Liver Neoplasms / Q000201:enzymology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010766:Phosphorylation / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D000072377:Syk Kinase
chemical_list: D000970:Antineoplastic Agents; D002227:Carbazoles; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; C081021:Go 6976; D011494:Protein Kinases; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse; D046988:Proteasome Endopeptidase Complex; D002945:Cisplatin