Inactivated FABP5 suppresses malignant progression of prostate cancer cells by inhibiting the activation of nuclear fatty acid receptor PPARγ.

Q2 Biochemistry, Genetics and Molecular Biology
Waseem Al-Jameel, Xiaojun Gou, Xi Jin, Jiacheng Zhang, Qiang Wei, Jianzhong Ai, Hong Li, Asmaa Al-Bayati, Angela Platt-Higgins, Andrew Pettitt, Philip S Rudland, Youqiang Ke
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引用次数: 20

Abstract

Previous study has suggested that the FABP5-PPARγ-signalling transduction pathway gradually replaces the androgen receptor activated pathway in promoting malignant progression of castration-resistant prostate cancer (CRPC) cells. To interfere with this newly discovered FABP5-related signalling pathway, we have produced a highly efficient recombinant FABP5 inhibitor, named dmrFABP5. Treatment with dmrFABP5 significantly supressed the proliferation, migration, invasion and colony formation of the highly malignant prostate cancer cells PC3-M in vitro. To test dmrFABP5's suppressive effect in CRPC, the human PC3-M cells were implanted orthotopically into the prostate gland of immunosuppressed mice to produce tumours. These mice were then treated with dmrFABP5 and produced a highly significant reduction of 100% in metastatic rate and a highly significant reduction of 13-fold in the average size of primary tumours. Immunocytochemial staining showed that the staining intensity of dmrFABP5 treated tumours was reduced by 67%. When tested in vitro, dmrFABP5 suppressed the cancer cells by blocking fatty acid stimulation of PPARγ, and thereby prevented it activating down-stream cancer-promoting or inhibiting cancer-suppressing genes. Our results show that the FABP5 inhibitor dmrFABP5 is a novel molecule for treatment of experimental CRPC and its inhibitory effect is much greater than that produced by SB-FI-26 reported in our previous work.

Abstract Image

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失活的FABP5通过抑制核脂肪酸受体PPARγ的激活来抑制前列腺癌细胞的恶性进展。
既往研究表明,fabp5 - ppar γ信号转导通路逐渐取代雄激素受体激活通路,促进去势抵抗性前列腺癌(CRPC)细胞的恶性进展。为了干扰这个新发现的FABP5相关信号通路,我们生产了一种高效的重组FABP5抑制剂,命名为dmrFABP5。dmrFABP5可显著抑制体外高度恶性前列腺癌细胞PC3-M的增殖、迁移、侵袭和集落形成。为了检测dmrFABP5对CRPC的抑制作用,我们将人PC3-M细胞原位植入免疫抑制小鼠的前列腺,使其产生肿瘤。然后用dmrFABP5治疗这些小鼠,转移率显著降低100%,原发肿瘤的平均大小显著降低13倍。免疫细胞化学染色显示dmrFABP5处理的肿瘤染色强度降低67%。在体外实验中,dmrFABP5通过阻断脂肪酸对PPARγ的刺激来抑制癌细胞,从而阻止其激活下游促癌或抑制抑癌基因。我们的研究结果表明,FABP5抑制剂dmrFABP5是一种治疗实验性CRPC的新分子,其抑制作用远远大于我们之前报道的SB-FI-26。
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来源期刊
Genes and Cancer
Genes and Cancer Biochemistry, Genetics and Molecular Biology-Genetics
CiteScore
3.90
自引率
0.00%
发文量
6
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