Downregulation of Critical Oncogenes by the Selective SK2 Inhibitor ABC294640 Hinders Prostate Cancer Progression.
Downregulation of Critical Oncogenes by the Selective SK2 Inhibitor ABC294640 Hinders Prostate Cancer Progression.
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DOI：
10.1158/1541-7786.mcr-14-0626
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发表时间：
2015-12
期刊：
影响因子：
--
通讯作者：
Smith CD
中科院分区：
文献类型：
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作者：
Schrecengost RS;Keller SN;Schiewer MJ;Knudsen KE;Smith CD
生物活性鞘脂 1-磷酸鞘氨醇 (S1P) 驱动癌症的几个标志性过程，使合成 S1P 的酶，即鞘氨醇激酶 1 和 2（SK1 和 SK2）成为癌症药物开发的重要分子靶标。 ABC294640是一流的SK2小分子抑制剂，可在体外和体内有效抑制癌细胞生长。鉴于 AR 和 Myc 是前列腺癌 (PCa) 中最广泛涉及的两种癌基因，并且鞘脂影响这两种蛋白质的信号传导，因此评估了使用 ABC294640 治疗 PCa 的治疗潜力。这项研究表明 ABC294640 消除了 PCa 生长和增殖所需的信号通路。主要研究结果证实 ABC294640 治疗早期和晚期 PCa 模型可下调 Myc 和 AR 表达和活性。这与生长、增殖和细胞周期进程的显着抑制相对应。最后，发现口服 ABC294640 可以显着阻碍异种移植肿瘤的生长。总之，这些临床前研究结果支持了这样的假设：SK2 活性是 PCa 功能所必需的，并且 ABC294640 代表了一种用于治疗早期和侵袭性 PCa 的新药物。
The bioactive sphingolipid sphingosine-1-phosphate (S1P) drives several hallmark processes of cancer, making the enzymes that synthesize S1P, i.e. sphingosine kinase 1 and 2 (SK1 and SK2), important molecular targets for cancer drug development. ABC294640 is a first-in-class SK2 small-molecule inhibitor that effectively inhibits cancer cell growth in vitro and in vivo. Given that AR and Myc are two of the most widely implicated oncogenes in prostate cancer (PCa), and that sphingolipids impact signaling by both proteins, the therapeutic potential for using ABC294640 in the treatment of PCa was evaluated. This study demonstrates that ABC294640 abrogates signaling pathways requisite for PCa growth and proliferation. Key findings validate that ABC294640 treatment of early stage and advanced PCa models downregulate Myc and AR expression and activity. This corresponds with significant inhibition of growth, proliferation, and cell cycle progression. Finally, oral administration of ABC294640 was found to dramatically impede xenograft tumor growth. Together, these pre-clinical findings support the hypotheses that SK2 activity is required for PCa function and that ABC294640 represents a new pharmacological agent for treatment of early stage and aggressive PCa.