Sangivamycin and its derivatives inhibit Haspin-Histone H3-survivin signaling and induce pancreatic cancer cell death
Sangivamycin and its derivatives inhibit Haspin-Histone H3-survivin signaling and induce pancreatic cancer cell death
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DOI：
10.1038/s41598-019-53223-0
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发表时间：
2019-11-12
影响因子：
4.6
通讯作者：
Storz, Peter
中科院分区：
文献类型：
--
作者：
Bastea, Ligia I.;Hollant, Laeticia M. A.;Storz, Peter
目前胰腺癌患者的治疗选择是次优的，导致五年生存率约为9%。治疗的困难是由于免疫抑制性、纤维化肿瘤微环境阻止药物到达肿瘤细胞，但也由于现有FDA批准的化疗化合物的疗效有限。我们在这里表明，核苷类似物桑吉瓦霉素和其密切相关的化合物丰卡霉素靶向PDA细胞系，并显着更有效地比吉西他滨。使用KINOMEscan筛选，我们鉴定了在PDA细胞系和人PDA样品中过表达的激酶Haspin作为两种化合物的主要靶点。Haspin的抑制导致组蛋白H3磷酸化减少并阻止组蛋白H3与存活素结合，从而提供了桑伐霉素如何靶向细胞增殖、有丝分裂和诱导凋亡性细胞死亡的机制见解。在小鼠原位移植肿瘤中，桑伐霉素可有效降低已建立肿瘤的生长。综上所述，我们表明桑吉瓦霉素及其衍生物是治疗PDA的一种有效的新选择。
Current treatment options for patients with pancreatic cancer are suboptimal, resulting in a five year survival rate of about 9%. Difficulties with treatment are due to an immunosuppressive, fibrotic tumor microenvironment that prevents drugs from reaching tumor cells, but also to the limited efficacy of existing FDA-approved chemotherapeutic compounds. We here show that the nucleoside analog Sangivamycin and its closely-related compound Toyocamycin target PDA cell lines, and are significantly more efficient than Gemcitabine. Using KINOMEscan screening, we identified the kinase Haspin, which is overexpressed in PDA cell lines and human PDA samples, as a main target for both compounds. Inhibition of Haspin leads to a decrease in Histone H3 phosphorylation and prevents Histone H3 binding to survivin, thus providing mechanistic insight of how Sangivamycin targets cell proliferation, mitosis and induces apoptotic cell death. In orthotopically implanted tumors in mice, Sangivamycin was efficient in decreasing the growth of established tumors. In summary, we show that Sangivamycin and derivatives can be an efficient new option for treatment of PDA.