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首页> 外文期刊>Biochemical Pharmacology >Thiostrepton is an inducer of oxidative and proteotoxic stress that impairs viability of human melanoma cells but not primary melanocytes
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Thiostrepton is an inducer of oxidative and proteotoxic stress that impairs viability of human melanoma cells but not primary melanocytes

机译：硫排蛋白是氧化和蛋白毒性应激的诱导物，其损害人黑素瘤细胞但不损害原代黑素细胞的活力

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Pharmacological induction of oxidative and proteotoxic stress has recently emerged as a promising strategy for chemotherapeutic intervention targeting cancer cells. Guided by a differential phenotypic drug screen for novel lead compounds that selectively induce melanoma cell apoptosis without compromising viability of primary human melanocytes, we have focused on the cyclic pyridinyl-polythiazolyl peptide-antimicrobial thiostrepton. Using comparative gene expression-array analysis, the early cellular stress response induced by thiostrepton was examined in human A375 metastatic melanoma cells and primary melanocytes. Thiostrepton displayed selective antimelanoma activity causing early induction of proteotoxic stress with massive upregulation of heat shock (HSPA6, HSPA1A, DNAJB4, HSPB1, HSPH1, HSPA1L, CRYAB, HSPA5, DNAJA1), oxidative stress (HMOX1, GSR, SOD1), and ER stress response (DDIT3) gene expression, confirmed by immunodetection (Hsp70, Hsp70B′, HO-1, phospho-eIF2α). Moreover, upregulation of p53, proapoptotic modulation of Bcl-2 family members (Bax, Noxa, Mcl-1, Bcl-2), and induction of apoptotic cell death were observed. Thiostrepton rapidly induced cellular oxidative stress followed by inactivation of chymotrypsin-like proteasomal activity and melanoma cell-directed accumulation of ubiquitinated proteins, not observed in melanocytes that were resistant to thiostrepton-induced apoptosis. Proteotoxic and apoptogenic effects were fully antagonized by antioxidant intervention. In RPMI 8226 multiple myeloma cells, known to be exquisitely sensitive to proteasome inhibition, early proteotoxic and apoptogenic effects of thiostrepton were confirmed by array analysis indicating pronounced upregulation of heat shock response gene expression. Our findings demonstrate that thiostrepton displays dual activity as a selective prooxidant and proteotoxic chemotherapeutic, suggesting feasibility of experimental intervention targeting metastatic melanoma and other malignancies including multiple myeloma.
机译：氧化和蛋白毒性应激的药理诱导最近已成为针对癌细胞的化学疗法干预的有前途的策略。通过针对新的先导化合物的差异表型药物筛选，该先导化合物可选择性诱导黑素瘤细胞凋亡而不会损害人类原代黑素细胞的生存能力，我们的研究重点是环状吡啶基-聚噻唑基肽-抗硫链球菌。使用比较基因表达阵列分析，在人A375转移性黑素瘤细胞和原代黑素细胞中检查了由硫链丝菌肽诱导的早期细胞应激反应。硫排蛋白显示选择性的炭黑素瘤活性，引起蛋白毒性应激的早期诱导，并大量上调热休克（HSPA6，HSPA1A，DNAJB4，HSPB1，HSPH1，HSPA1L，CRYAB，HSPA5，DNAJA1），氧化应激（HMOX1，GSR，SOD1）和ER应激免疫检测（Hsp70，Hsp70B'，HO-1，磷酸化-eIF2α）证实了其应答（DDIT3）基因表达。此外，观察到p53的上调，Bcl-2家族成员（Bax，Noxa，Mcl-1，Bcl-2）的凋亡调节和凋亡细胞死亡的诱导。硫排蛋白迅速诱导细胞氧化应激，随后灭活了胰凝乳蛋白酶样蛋白酶体活性和黑色素细胞定向的泛素化蛋白积聚，而在对硫代链霉菌素诱导的细胞凋亡具有抗性的黑素细胞中则未观察到。抗氧化剂干预可完全拮抗蛋白毒性和凋亡作用。在RPMI 8226中，已知对蛋白酶体抑制作用极为敏感的多发性骨髓瘤细胞，通过阵列分析证实了硫链蛋白原的早期蛋白毒性和凋亡作用，表明热休克反应基因表达明显上调。我们的发现表明，巯基链霉菌素作为选择性的抗氧化剂和蛋白毒性化疗剂具有双重活性，表明针对转移性黑素瘤和其他恶性肿瘤（包括多发性骨髓瘤）进行实验干预的可行性。

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