CHK1 targets spleen tyrosine kinase (L) for proteolysis in hepatocellular carcinoma
Jian Hong, … , Yi-Xin Zeng, Tiebang Kang
Jian Hong, … , Yi-Xin Zeng, Tiebang Kang
Published May 15, 2012
Citation Information: J Clin Invest. 2012;122(6):2165-2175. https://doi.org/10.1172/JCI61380.
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Research Article Oncology

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

Jian Hong, Kaishun Hu, Yunfei Yuan, Yi Sang, Qiangui Bu, Guihua Chen, Longjun Yang, Binkui Li, Pinzhu Huang, Dongtai Chen, Yi Liang, Ruhua Zhang, Jingxuan Pan, Yi-Xin Zeng, Tiebang Kang

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Figure 5

Inhibition of CHK1 suppresses tumorigenicity through the CHK1/SYK(L) pathway in HCC in vitro and in vivo.

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Inhibition of CHK1 suppresses tumorigenicity through the CHK1/SYK(L) pat...
(A) SMMC7721 stable cell lines used in Figure 3A were treated with GÖ6976 (100 nM) or DMSO (Con) as indicated for different amounts of time and were subjected to an MTT assay (n = 3). The dots represent the mean, while the bars indicate the SEM. (B) SMMC7721 stable cell lines were injected into the flanks of nude mice and incubated for 6 days, and then the mice were treated with GÖ6976 (100 nM) or DMSO. The tumor volumes were measured and recorded every 3 days, and tumor growth curves were created for each group (n = 14). Dots represent the mean, while bars indicate the SEM. *P < 0.05, using Student’s t test. (C) On day 27, the xenografts were excised from mice and weighed, as shown in Supplemental Figure 9. Each dot represents a tumor weight; the mean tumor weights of each group were indicated by solid lines (left panel; n = 14), and P values were obtained using the Student’s t test.