Patulin and LL-Z1640-2 induce apoptosis of cancer cells by decreasing endogenous protein levels of Zic family member 5.
Patulin and LL-Z1640-2 induce apoptosis of cancer cells by decreasing endogenous protein levels of Zic family member 5.
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DOI：
10.1111/jcmm.17598
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发表时间：
2022-11
影响因子：
5.3
通讯作者：
中科院分区：
文献类型：
--
作者：
Zic家族成员5 （ZIC5）是一种促进多种癌症细胞存活的转录因子。由于ZIC5在正常成人组织中的表达水平极低，因此它是一个潜在的治疗靶点。在这项研究中，我们筛选了一个包含3398种化合物的化学文库，其中包括预先存在的药物和已知作用的化合物，以鉴定ZIC5抑制剂。在第一次筛选中，18种命中化合物在过表达GFP标记ZIC5的黑色素瘤A375细胞中降低了GFP强度。在第二次筛选中，鉴定出5种降低A375细胞中ZIC5蛋白水平的化合物。其中，LL‐Z1640‐2和展霉素选择性地诱导表达ZIC5的黑色素瘤细胞凋亡，而在未检测到ZIC5表达的正常人黑色素细胞中仅诱导极低水平的凋亡。LL‐Z1640‐2和展霉素也可诱导BRAF抑制剂耐药黑色素瘤、胰腺癌、胆管癌和结直肠癌细胞凋亡。ZIC5过表达可挽救LL‐Z1640‐2‐和展霉素介导的黑色素瘤增殖抑制。这些结果表明LL‐Z1640‐2和展霉素是有希望降低ZIC5表达诱导癌细胞凋亡的化合物。
Zic family member 5 (ZIC5) is a transcription factor that promotes the survival of several cancer cell types. As ZIC5 is expressed at minimal levels in normal human adult tissues, it is a potential therapeutic target. In this study, we screened a chemical library containing 3398 compounds that includes pre‐existing drugs and compounds with known effects to identify ZIC5 inhibitors. In the first screening, 18 hit compounds decreased GFP intensity in melanoma A375 cells overexpressing GFP‐tagged ZIC5. In the second screening, five compounds that attenuated ZIC5 protein levels in A375 cells were identified. Among them, LL‐Z1640‐2 and patulin selectively induced apoptosis in melanoma cells expressing ZIC5, while only inducing very low levels of apoptosis in normal human melanocytes, which have no detectable ZIC5 expression. LL‐Z1640‐2 and patulin also induced apoptosis in BRAF inhibitor‐resistant melanoma, pancreatic cancer, cholangiocarcinoma and colorectal cancer cells. LL‐Z1640‐2‐ and patulin‐mediated suppression of melanoma proliferation were rescued by ZIC5 overexpression. These results suggest that LL‐Z1640‐2 and patulin are promising compounds that decrease ZIC5 expression to induce apoptosis in cancer cells.
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