Targeting of HER/ErbB family proteins using broad spectrum Sec61 inhibitors coibamide A and apratoxin A

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Kazemi , S , Kawaguchi , S , Badr , C E , Mattos , D R , Ruiz-Saenz , A , Serrill , J D , Moasser , M M , Dolan , B P , Paavilainen , V O , Oishi , S , McPhail , K L & Ishmael , J E 2021 , ' Targeting of HER/ErbB family proteins using broad spectrum Sec61 inhibitors coibamide A and apratoxin A ' , Biochemical Pharmacology , vol. 183 , 114317 . https://doi.org/10.1016/j.bcp.2020.114317

Title: Targeting of HER/ErbB family proteins using broad spectrum Sec61 inhibitors coibamide A and apratoxin A
Author: Kazemi, Soheila; Kawaguchi, Shinsaku; Badr, Christian E.; Mattos, Daphne R.; Ruiz-Saenz, Ana; Serrill, Jeffrey D.; Moasser, Mark M.; Dolan, Brian P.; Paavilainen, Ville O.; Oishi, Shinya; McPhail, Kerry L.; Ishmael, Jane E.
Contributor organization: Institute of Biotechnology
Biosciences
University of Helsinki
Date: 2021-01
Language: eng
Number of pages: 16
Belongs to series: Biochemical Pharmacology
ISSN: 0006-2952
DOI: https://doi.org/10.1016/j.bcp.2020.114317
URI: http://hdl.handle.net/10138/326607
Abstract: 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 Aor 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. Timeand 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.
Subject: ErbB
HER
Signal peptide
Kinase inhibitor
Coibamide A
Apratoxin A
EPIDERMAL-GROWTH-FACTOR
FACTOR-RECEPTOR MUTATIONS
PHOSPHATIDYLINOSITOL 3-KINASE
BIOLOGICAL EVALUATION
ERBB RECEPTORS
CANCER-THERAPY
BREAST-CANCER
TRANSLOCATION
POTENT
SUBSTRATE
1182 Biochemistry, cell and molecular biology
317 Pharmacy
Peer reviewed: Yes
Rights: cc_by_nc_nd
Usage restriction: openAccess
Self-archived version: publishedVersion


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