PDF(Pubmed)
Abstract：
Ciliogenesis-associated kinase 1 (CILK1) plays a key role in the ciliogenesis and ciliopathies. It remains totally unclear whether CILK1 is involved in tumor progression and therapy resistance. Here, we report that the aberrant high-expression of CILK1 in breast cancer is required for tumor cell proliferation and chemoresistance. Two compounds, CILK1-C30 and CILK1-C28, were identified with selective inhibitory effects towards the Tyr-159/Thr-157 dual-phosphorylation of CILK1, pharmacological inhibition of CILK1 significantly suppressed tumor cell proliferation and overcame chemoresistance in multiple experimental models. Large-scale screen of CILK1 substrates confirmed that the kinase directly phosphorylates ERK1, which is responsible for CILK1-mediated oncogenic function. CILK1 is also indicated to be responsible for the chemoresistance of small-cell lung cancer cells. Our data highlight the importance of CILK1 in cancer, implicating that targeting CILK1/ERK1 might offer therapeutic benefit to cancer patients.
摘要：
纤毛发生相关激酶1（CILK1）在纤毛发生和纤毛病变中起关键作用。目前尚不清楚CILK1是否参与肿瘤进展和治疗抵抗。这里,我们报道，乳腺癌中CILK1的异常高表达是肿瘤细胞增殖和化疗耐药所必需的。两种化合物，CILK1-C30和CILK1-C28对CILK1的Tyr-159/Thr-157双重磷酸化具有选择性抑制作用，CILK1的药理抑制作用显着抑制了肿瘤细胞的增殖并克服了多种实验模型中的化学耐药性。对CILK1底物的大规模筛选证实，该激酶直接磷酸化ERK1，这负责CILK1介导的致癌功能。CILK1也被证明是小细胞肺癌细胞化学抗性的原因。我们的数据强调了CILK1在癌症中的重要性，暗示靶向CILK1/ERK1可能为癌症患者提供治疗益处。
