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

S Kazemi, S Kawaguchi, CE Badr, DR Mattos, Ana Ruiz Saenz, JD Serrill, MM Moasser, BP Dolan, VO Paavilainen, S Oishi, KL McPhail, JE Ishmael

Research output: Contribution to journalArticleAcademicpeer-review

14 Citations (Scopus)

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 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.

Original languageEnglish
Article number114317
JournalBiochemical Pharmacology
Volume183
DOIs
Publication statusPublished - Jan 2021

Bibliographical note

Funding Information:
We thank Dylan Nelson of the High-Throughput Screening Services Laboratory at Oregon State University (OSU) for excellent technical assistance and Dr. Conroy Sun (OSU) for helpful discussions. This work was supported at an early stage by the American Brain Tumor Association (JEI), an NIH Fogarty International Center ICBG grant TW006634-06 (KLM), NIH/NCI R01CA122216 (MMM), the OSU College of Pharmacy and an American Foundation for Pharmaceutical Education (AFPE) Pre-Doctoral Fellowship in the Pharmaceutical Sciences (JDS) and later by NIH/NIGMS R01GM132649 (VOP, SO, KLM, JEI) and NIH/NCCIH T32AT010131 (DRM). VOP is supported by Academy of Finland grants 289737, 314672 and 330255 and a grant from the Sigrid Juselius Foundation.

Publisher Copyright:
© 2020 The Authors

Research programs

  • EMC OR-01

Fingerprint

Dive into the research topics of 'Targeting of HER/ErbB family proteins using broad spectrum Sec61 inhibitors coibamide A and apratoxin A'. Together they form a unique fingerprint.

Cite this