Inhibitor SBFI26 suppresses the malignant progression of castration-resistant PC3-M cells by competitively binding to oncogenic FABP5.
Inhibitor SBFI26 suppresses the malignant progression of castration-resistant PC3-M cells by competitively binding to oncogenic FABP5.
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DOI：
10.18632/oncotarget.16055
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发表时间：
2017-05-09
期刊：
影响因子：
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通讯作者：
Ke Y
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文献类型：
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作者：
Al-Jameel W;Gou X;Forootan SS;Al Fayi MS;Rudland PS;Forootan FS;Zhang J;Cornford PA;Hussain SA;Ke Y
去势抵抗性前列腺癌在很大程度上不受羽毛激素治疗的影响，因此患者的前景是严峻的。在这里，我们使用一种方法来连接最近发现的致命弱点。本研究中建立的实验性治疗是基于最近的发现，即FABP 5-PPARγ-VEGF信号传导轴，而不是雄激素受体途径，在促进去势抵抗性前列腺癌细胞的恶性进展中起主导作用。已经通过使用化学抑制剂SBFI 26抑制FABP 5的生物活性在小鼠中建立了治疗。该抑制剂在体外可显著抑制PC 3-M细胞的增殖、迁移、侵袭和集落形成。它还对原位植入小鼠前列腺的癌细胞产生的转移和原发肿瘤产生了非常显著的抑制。抑制剂SBFI 26通过竞争性结合FABP 5抑制细胞脂肪酸摄取，在信号转导的初始阶段干扰FABP 5-PPARγ-信号通路。这避免了脂肪酸对PPARγ的刺激，并防止其激活下游调节的促癌基因。这种治疗去势抵抗性前列腺癌的全新实验方法与目前基于雄激素阻断疗法的治疗方法完全不同。
Castration resistant-prostate cancer is largely impervious to feather hormonal therapy and hence the outlook for patients is grim. Here we use an approach to attach the recently discovered Achilles heel. The experimental treatment established in this study is based on the recent discovery that it is the FABP5-PPARγ-VEGF signalling axis, rather than the androgen receptor pathway, played a dominant role in promoting the malignant progression of castration resistant prostate cancer cells. Treatments have been established in mice by suppressing the biological activity of FABP5 using a chemical inhibitor SBFI26. The inhibitor significantly suppressed the proliferation, migration, invasiveness and colony formation of PC3-M cells in vitro. It also produced a highly significant suppression of both the metastases and the primary tumours developed from cancer cells implanted orthotopically into the prostate glands of the mice. The inhibitor SBFI26 interferes with the FABP5-PPARγ- signalling pathway at the initial stage of the signal transduction by binding competitively to FABP5 to inhibit cellular fatty acid uptake. This avoids the fatty-acid stimulation of PPARγ and prevents it activating the down-stream regulated cancer-promoting genes. This entirely novel experimental approach to treating castration- resistant prostate cancer is completely different from current treatments that are based on androgen-blockade therapy.