A plant alkaloid, veratridine, potentiates cancer chemosensitivity by UBXN2A-dependent inhibition of an oncoprotein, mortalin-2.
A plant alkaloid, veratridine, potentiates cancer chemosensitivity by UBXN2A-dependent inhibition of an oncoprotein, mortalin-2.
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DOI：
10.18632/oncotarget.4452
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发表时间：
2015-09-15
期刊：
影响因子：
--
通讯作者：
Rezvani K
中科院分区：
文献类型：
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作者：
Abdullah A;Sane S;Branick KA;Freeling JL;Wang H;Zhang D;Rezvani K
藜芦定（Veratridine，VTD）是一种来源于百合科植物的生物碱，具有抗肿瘤作用，但其作用靶点的研究尚不深入。使用高通量药物筛选，我们发现VTD增强UBXN 2A的反式激活，导致UBXN 2A在细胞质中的上调，其中UBXN 2A结合并抑制癌蛋白mortalin-2（mot-2）。VTD处理的癌细胞以UBXN 2A和mot-2依赖性方式经历细胞死亡。VTD的细胞毒性功能是分级依赖性的，并且与标准化疗的次优剂量5-氟尿嘧啶（5-FU）和依托泊苷的联合治疗显示出协同效应，导致更高的治疗效果。VTD可能通过UBXN 2A依赖性抑制mot-2影响CD 44+干细胞。UBXN 2A的VTD依赖性表达是设计用于结肠癌治疗的新策略的潜在候选者，因为：1）在50%的结肠癌患者中，肿瘤组织中的UBXN 2A蛋白水平显著低于邻近正常组织中的那些。2)在非癌细胞中，mot-2蛋白质的胞质表达非常低;因此，VTD可以产生肿瘤特异性毒性，而正常细胞保持完整。3)最后，VTD或其修饰的类似物提供了一种有价值的辅助化疗策略，以提高基于5-FU的化疗对携带WT-p53的结肠癌患者的疗效。
Veratridine (VTD), an alkaloid derived from the Liliaceae plant shows anti-tumor effects; however, its molecular targets have not been thoroughly studied. Using a high-throughput drug screen, we found that VTD enhances transactivation of UBXN2A, resulting in upregulation of UBXN2A in the cytoplasm, where UBXN2A binds and inhibits the oncoprotein mortalin-2 (mot-2). VTD-treated cancer cells undergo cell death in UBXN2A- and mot-2-dependent manners. The cytotoxic function of VTD is grade-dependent, and the combined treatment with a sub-optimal dose of the standard chemotherapy, 5-Fluorouracil (5-FU) and etoposide, demonstrated a synergistic effect, resulting in higher therapeutic efficacy. VTD influences the CD44+ stem cells, possibly through UBXN2A-dependent inhibition of mot-2. The VTD-dependent expression of UBXN2A is a potential candidate for designing novel strategies for colon cancer treatment because: 1) In 50% of colon cancer patients, UBXN2A protein levels in tumor tissues are significantly lower than those in the adjacent normal tissues. 2) Cytoplasmic expression of the mot-2 protein is very low in non-cancerous cells; thus, VTD can produce tumor-specific toxicity while normal cells remain intact. 3) Finally, VTD or its modified analogs offer a valuable adjuvant chemotherapy strategy to improve the efficacy of 5-FU-based chemotherapy for colon cancer patients harboring WT-p53.