Fatostatin Inhibits Cancer Cell Proliferation by Affecting Mitotic Microtubule Spindle Assembly and Cell Division
Fatostatin Inhibits Cancer Cell Proliferation by Affecting Mitotic Microtubule Spindle Assembly and Cell Division
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DOI：
10.1074/jbc.c116.737346
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发表时间：
2016-08-01
影响因子：
4.8
通讯作者：
Torres, Jorge Z.
中科院分区：
文献类型：
--
作者：
Gholkar, Ankur A.;Cheung, Keith;Torres, Jorge Z.
固醇调节元件结合蛋白（SREBP）转录因子已成为代谢性疾病和癌症治疗中具有吸引力的药理学抑制靶点。SREBP对于脂质和胆固醇的产生和代谢至关重要，而脂质和胆固醇对于细胞稳态和细胞增殖至关重要。Fatostatin是最近发现的SREBP裂解激活蛋白（SCAP）的特异性抑制剂，SREBP裂解激活蛋白是SREBP激活所必需的。Fatostatin具有抑制癌细胞增殖、侵袭和迁移的抗肿瘤特性，可使癌细胞阻滞于G（2）/M期。虽然法托他汀已被视为一种抗肿瘤剂，由于其抑制SREBP和其对脂质代谢的影响，我们表明，法托他汀的抗癌特性也可以归因于其抑制细胞分裂。我们分析了SREBP活性抑制剂包括法托他汀、PF-429242和桦木醇对细胞周期的影响，并确定只有法托他汀具有抗有丝分裂特性。法托他汀抑制微管蛋白聚合，阻止细胞有丝分裂，激活纺锤体组装检查点，并引发有丝分裂灾难和降低细胞活力。因此，法托他汀抑制SREBP活性和细胞分裂的能力可以证明有益于治疗侵袭性类型的癌症，如胶质母细胞瘤，其具有升高的脂质代谢和快速增殖速率，并且通常对当前的抗癌疗法产生抗性。
The sterol regulatory element-binding protein (SREBP) transcription factors have become attractive targets for pharmacological inhibition in the treatment of metabolic diseases and cancer. SREBPs are critical for the production and metabolism of lipids and cholesterol, which are essential for cellular homeostasis and cell proliferation. Fatostatin was recently discovered as a specific inhibitor of SREBP cleavage-activating protein (SCAP), which is required for SREBP activation. Fatostatin possesses antitumor properties including the inhibition of cancer cell proliferation, invasion, and migration, and it arrests cancer cells in G(2)/M phase. Although Fatostatin has been viewed as an antitumor agent due to its inhibition of SREBP and its effect on lipid metabolism, we show that Fatostatin's anticancer properties can also be attributed to its inhibition of cell division. We analyzed the effect of SREBP activity inhibitors including Fatostatin, PF-429242, and Betulin on the cell cycle and determined that only Fatostatin possessed antimitotic properties. Fatostatin inhibited tubulin polymerization, arrested cells in mitosis, activated the spindle assembly checkpoint, and triggered mitotic catastrophe and reduced cell viability. Thus Fatostatin's ability to inhibit SREBP activity and cell division could prove beneficial in treating aggressive types of cancers such as glioblastomas that have elevated lipid metabolism and fast proliferation rates and often develop resistance to current anticancer therapies.