Targeting of HER/ErbB family proteins using broad spectrum Sec61 inhibitors coibamide A and apratoxin A.
Targeting of HER/ErbB family proteins using broad spectrum Sec61 inhibitors coibamide A and apratoxin A.
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DOI：
10.1016/j.bcp.2020.114317
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发表时间：
2021-01
影响因子：
5.8
通讯作者：
Ishmael JE
中科院分区：
文献类型：
--
作者：
Kazemi S;Kawaguchi S;Badr CE;Mattos DR;Ruiz-Saenz A;Serrill JD;Moasser MM;Dolan BP;Paavilainen VO;Oishi S;McPhail KL;Ishmael JE
Coibamide A是一种有效的癌细胞毒素，并且是一组选择的天然产物之一，其通过直接抑制Sec 61蛋白转位子来抑制蛋白质进入分泌途径。许多Sec 61客户蛋白一旦被运输到细胞内或细胞外的最终目的地，就成为临床相关的药物靶标，然而使用Sec 61抑制剂来阻断特定蛋白的早期生物合成仍处于临床前阶段。在本研究中，我们评估了coibamide A对代表性乳腺癌和肺癌细胞类型中的人表皮生长因子受体（HER，ErbB）蛋白的作用。选择HER用于本研究，因为它们代表Sec 61客户端家族，该家族在人类癌症中经常失调，包括coibamide敏感细胞类型。尽管coibamide A以假定的底物非选择性方式抑制广泛的Sec 61底物蛋白的生物合成，但内源性HER 3（ErbB-3）和EGFR（ErbB-1）蛋白对coibamide A和相关Sec 61抑制剂阿曲毒素A比HER 2（ErbB-2）更敏感。尽管有这种敏感性等级顺序（HER 3> EGFR > HER 2），但coibamide A的Sec 61依赖性抑制足以降低HER 2的细胞表面表达。我们报告说，coibamide A或阿曲毒素A介导的阻断HER 3进入分泌途径是不太可能介导的HER 3信号肽单独。HER 3（G11 L/S15 L）对高度底物选择性的cotransin类似物CT 8完全耐药，比野生型HER 3更具耐药性，但仅在低浓度coibamide A（3 nM）下; HER 3（G11 L/S15 L）表达受到更高浓度的天然产物的抑制。HER蛋白表达的时间和浓度依赖性降低会导致乳腺癌和肺癌细胞类型中AKT/MAPK信号传导的相应减少以及细胞活力的丧失。考巴胺A分别增强了小分子激酶抑制剂拉帕替尼和厄洛替尼在乳腺癌和肺癌细胞类型中的细胞毒性功效。这些数据表明，Sec 61功能的天然产物调节剂具有作为化学探针的价值，以询问治疗抗性人类癌症中的HER/ErbB信号传导。
Coibamide A is a potent cancer cell toxin and one of a select group of natural products that inhibit protein entry into the secretory pathway via a direct inhibition of the Sec61 protein translocon. Many Sec61 client proteins are clinically relevant drug targets once trafficked to their final destination in or outside the cell, however the use of Sec61 inhibitors to block early biosynthesis of specific proteins is at a pre-clinical stage. In the present study we evaluated the action of coibamide A against human epidermal growth factor receptor (HER, ErbB) proteins in representative breast and lung cancer cell types. HERs were selected for this study as they represent a family of Sec61 clients that is frequently dysregulated in human cancers, including coibamide-sensitive cell types. Although coibamide A inhibits biogenesis of a broad range of Sec61 substrate proteins in a presumed substrate-nonselective manner, endogenous HER3 (ErbB-3) and EGFR (ErbB-1) proteins were more sensitive to coibamide A, and the related Sec61 inhibitor apratoxin A, than HER2 (ErbB-2). Despite this rank order of sensitivity (HER3 > EGFR > HER2), Sec61-dependent inhibition by coibamide A was sufficient to decrease cell surface expression of HER2. We report that coibamide A- or apratoxin A-mediated block of HER3 entry into the secretory pathway is unlikely to be mediated by the HER3 signal peptide alone. HER3 (G11L/S15L), that is fully resistant to the highly substrate-selective cotransin analogue CT8, was more resistant than wild-type HER3 but only at low coibamide A (3 nM) concentrations; HER3 (G11L/S15L) expression was inhibited by higher concentrations of either natural product. Time- and concentration-dependent decreases in HER protein expression induced a commensurate reduction in AKT/MAPK signaling in breast and lung cancer cell types and loss in cell viability. Coibamide A potentiated the cytotoxic efficacy of small molecule kinase inhibitors lapatinib and erlotinib in breast and lung cancer cell types, respectively. These data indicate that natural product modulators of Sec61 function have value as chemical probes to interrogate HER/ErbB signaling in treatment-resistant human cancers.
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影响因子：
3.7
作者：
Badr CE;Hewett JW;Breakefield XO;Tannous BA
通讯作者：
Tannous BA
影响因子：
64.8
作者：
Besemer, J;Harant, H;Lindley, IJD
通讯作者：
Lindley, IJD
影响因子：
16
作者：
Garrett, TPJ;McKern, NM;Ward, CW
通讯作者：
Ward, CW
影响因子：
11.4
作者：
GrausPorta, D;Beerli, RR;Hynes, NE
通讯作者：
Hynes, NE
影响因子：
28.2
作者：
Bose R;Kavuri SM;Searleman AC;Shen W;Shen D;Koboldt DC;Monsey J;Goel N;Aronson AB;Li S;Ma CX;Ding L;Mardis ER;Ellis MJ
通讯作者：
Ellis MJ