Lymphocyte antigen 6K signaling to aurora kinase promotes advancement of the cell cycle and the growth of cancer cells, which is inhibited by LY6K-NSC243928 interaction
Lymphocyte antigen 6K signaling to aurora kinase promotes advancement of the cell cycle and the growth of cancer cells, which is inhibited by LY6K-NSC243928 interaction
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DOI：
10.1016/j.canlet.2023.216094
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发表时间：
2023-02-20
期刊：
影响因子：
9.7
通讯作者：
Upadhyay，Geeta
中科院分区：
文献类型：
--
作者：
Selvanesan，Benson Chellakkan;Varghese，Sheelu;Upadhyay，Geeta
淋巴细胞抗原6K(LY6K)是一种与GPI连接的小蛋白，通常在睾丸中表达。LY6K的高表达与许多实体癌的不良生存结局显著相关，包括乳腺癌、卵巢癌、胃肠道癌、头颈部癌、脑癌、膀胱癌和肺癌。LY6K是癌细胞中ERK-AKT和转化生长因子-β途径所必需的，也是体内肿瘤生长所必需的。在这篇报道中，我们描述了LY6K通过极光B激酶及其底物组蛋白H3信号轴在有丝分裂和胞质分裂中的新作用。进一步，我们描述了小分子NSC243928与LY6K蛋白相互作用的结构基础，以及LY6K-NSC243928相互作用对LY6K-AURORA B信号在细胞周期进程中的干扰。总体而言，通过NSC243928破坏LY6K功能会导致胞质分裂失败、多核细胞、DNA损伤、衰老和癌细胞凋亡。LY6K不是重要器官功能所必需的，因此抑制LY6K信号是缺乏靶向治疗的难治性癌症(如三阴性乳腺癌)的理想治疗方法。
Lymphocyte antigen 6K (LY6K) is a small GPI-linked protein that is normally expressed in testes. Increased expression of LY6K is significantly associated with poor survival outcomes in many solid cancers, including cancers from breast, ovary, gastrointestinal tract, head and neck, brain, bladder, and lung. LY6K is required for ERK-AKT and TGF-β pathways in cancer cells and is required for in vivo tumor growth. In this report, we describe a novel role for LY6K in mitosis and cytokinesis through aurora B kinase and its substrate histone H3 signaling axis. Further, we describe the structural basis of the molecular interaction of small molecule NSC243928 with LY6K protein and the disruption of LY6K-aurora B signaling in cell cycle progression due to LY6K-NSC243928 interaction. Overall, disruption of LY6K function via NSC243928 led to failed cytokinesis, multinucleated cells, DNA damage, senescence, and apoptosis of cancer cells. LY6K is not required for vital organ function, thus inhibition of LY6K signaling is an ideal therapeutic approach for hard-to-treat cancers that lack targeted therapy such as triple negative breast cancer.