A unique amidoanthraquinone derivative displays antiproliferative activity against human hormone-refractory metastatic prostate cancers through activation of LKB1-AMPK-mTOR signaling pathway
A unique amidoanthraquinone derivative displays antiproliferative activity against human hormone-refractory metastatic prostate cancers through activation of LKB1-AMPK-mTOR signaling pathway
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DOI：
10.1007/s00210-014-0998-9
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发表时间：
2014-10-01
影响因子：
3.6
通讯作者：
Guh, Jih-Hwa
中科院分区：
文献类型：
--
作者：
Hsu, Jui-Ling;Liu, Shih-Ping;Guh, Jih-Hwa
激素难治性转移性前列腺癌（Hormone-refracted metastatic prostate cancer，HRMPC）是一种具有转移性且对激素治疗有抵抗力的肿瘤，是临床治疗中的一个难题。基于蒽醌的天然产物和合成化合物已显示出抗癌活性。然而，心脏毒性是这些化合物的主要不良反应。CC-36是一种独特的蒽醌衍生物，在HRMPC中显示出比H9c2心肌细胞和正常前列腺细胞更高的抗增殖活性，选择性分别为5倍和12倍。CC-36导致细胞周期G1期阻滞，并上调p21和下调cyclin D1和cyclin E表达水平。免疫沉淀和Western blotting分析显示CC-36可诱导TSC 1/TSC 2结合增加，并抑制哺乳动物雷帕霉素靶蛋白（mTOR）（Ser2448）和p70核糖体蛋白S6激酶（p70S6K）（Thr389）的磷酸化，表明CC-36可抑制这两种激酶的活性。CC-36诱导肝激酶B1（LKB 1）在Thr189磷酸化，导致LKB 1从细胞核易位到胞质溶胶进行AMPK α磷酸化（Thr172）和激酶激活。使用小干扰RNA（siRNA）技术与LKB 1敲低来验证信号通路。MK 2206（一种特异性Akt抑制剂）与CC-36的联合处理显示出PC-3细胞中的协同凋亡，表明LKB 1激活剂的潜在组合策略。综上所述，数据表明CC-36通过激活LKB1-AMPK途径显示抗HRMPC活性，导致mTOR信号传导的抑制和细胞周期G1期阻滞的诱导。Akt抑制剂与通过LKB1-AMPK-mTOR通路起作用的药物的联合使用是HRMPC治疗的潜在策略。
Hormone-refractory metastatic prostate cancer (HRMPC), which is metastatic and resistant to hormone therapy, is an intractable problem in clinical treatment. Anthraquinone-based natural products and synthetic compounds have shown anticancer activity. However, cardiac toxicity is a major adverse reaction in these compounds. CC-36, a unique anthraquinone derivative, displayed higher antiproliferative activity in HRMPC than that in H9c2 cardiomyoblasts and normal prostate cells with the selectivity of five and twelve times, respectively. CC-36 caused G1 arrest of the cell cycle associated with an upregulation of p21 and downregulated levels of cyclin D1 and cyclin E expressions. Immunoprecipitation assay and Western blotting analysis showed that CC-36 triggered an increase of TSC1/TSC2 association and suppressed the phosphorylation of mammalian target of rapamycin (mTOR) (Ser2448) and p70 ribosomal protein S6 kinase (p70S6K) (Thr389), indicating the inhibition of both kinases' activities. CC-36 induced liver kinase B1 (LKB1) phosphorylation at Thr189, leading to LKB1 translocation from nucleus to cytosol for AMPK alpha phosphorylation (Thr172) and the kinase activation. The signaling pathway was validated using small interfering RNA (siRNA) technique with LKB1 knockdown. The combination treatment of MK2206 (a specific Akt inhibitor) with CC-36 showed a synergistic apoptosis in PC-3 cells indicating a potential combination strategy for LKB1 activators. Taken together, the data suggest that CC-36 displays anti-HRMPC activity through the activation of LKB1-AMPK pathway, leading to an inhibition of mTOR signaling and the induction of G1 arrest of the cell cycle. The combination use of Akt inhibitors with agents acting through LKB1-AMPK-mTOR pathway is a potential strategy for HRMPC treatment.