Kolavenic acid analog restores growth in HSET-overproducing fission yeast cells and multipolar mitosis in MDA-MB-231 human cells
Kolavenic acid analog restores growth in HSET-overproducing fission yeast cells and multipolar mitosis in MDA-MB-231 human cells
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DOI：
10.1016/j.bmc.2019.115154
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发表时间：
2020-01-01
影响因子：
3.5
通讯作者：
Kimura, Ken-ichi
中科院分区：
文献类型：
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作者：
Kurisawa, Naoaki;Yukawa, Masashi;Kimura, Ken-ichi
虽然癌细胞经常携带多余的中心体，但它们通过中心体聚集形成伪双极纺锤体，而不是致命的多极纺锤体，从而避免了细胞死亡。Kinesin-14 HSET/KIFC1是参与中心体聚集的关键蛋白。因此，一种靶向HSET的化合物可能会以靶向的方式抑制癌细胞的增殖。在这里，我们报道了三种从紫苏花中提取的天然化合物，它们可以恢复裂变酵母细胞的生长，表现出致命的HSET过剩（阳性筛选），即紫苏花酸（SA） (1)， kolavenic酸类似物（KAA: 6 β -tigloyloxykolavenic酸的C-9和C-10的立体异构体）(2)和kolavenic酸（KA）(3)。这三种化合物都抑制了分裂酵母细胞的死亡，并使有丝分裂纺锤体从单极形态转变为双极形态。化合物2对过量产生hset的酵母细胞的抑制作用最强，也抑制了MDA-MB-231人乳腺腺癌细胞中含有大量多余中心体的中心体聚集。这些天然化合物可作为生物探针用于HSET功能的研究。此外，化合物2是开发新型癌症治疗药物的主要竞争者。
Although cancer cells often harbor supernumerary centrosomes, they form pseudo-bipolar spindles via centrosome clustering, instead of lethal multipolar spindles, and thus avoid cell death. Kinesin-14 HSET/KIFC1 is a crucial protein involved in centrosome clustering. Accordingly, a compound that targets HSET could potentially inhibit cancer cell proliferation in a targeted manner. Here, we report three natural compounds derived from Solidago altissima that restored the growth of fission yeast cells exhibiting lethal HSET overproduction (positive screening), namely solidagonic acid (SA) (1), kolavenic acid analog (KAA: a stereo isomer at C-9 and C-10 of 6 beta-tigloyloxykolavenic acid) (2), and kolavenic acid (KA) (3). All three compounds suppressed fission yeast cell death and enabled reversion of the mitotic spindles from a monopolar to bipolar morphology. Compound 2, which exerted the strongest activity against HSET-overproducing yeast cells, also inhibited centrosome clustering in MDA-MB-231 human breast adenocarcinoma cells, which contained large numbers of supernumerary centrosomes. These natural compounds may be useful as bioprobes in studies of HSET function. Moreover, compound 2 is a prime contender in the development of novel agents for cancer treatment.