Pharmacological induction of selective endoplasmic reticulum retention as a strategy for cancer therapy

Mohamed Mahameed; Shatha Boukeileh; Akram Obiedat; Odai Darawshi; Priya Dipta; Amit Rimon; Gordon McLennan; Rosi Fassler; Dana Reichmann; Rotem Karni; Christian Preisinger; Thomas Wilhelm; Michael Huber; Boaz Tirosh

doi:10.1038/s41467-020-15067-5

Pharmacological induction of selective endoplasmic reticulum retention as a strategy for cancer therapy

Nat Commun. 2020 Mar 11;11(1):1304. doi: 10.1038/s41467-020-15067-5.

Authors

Affiliations

¹ Institute for Drug Research, The Hebrew University of Jerusalem, Jerusalem, Israel.
² Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.
³ The Alexander Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Safra Campus Givat Ram, Jerusalem, Israel.
⁴ Department of Biochemistry, Faculty of Medicine, IMRIC, The Hebrew University of Jerusalem, Jerusalem, Israel.
⁵ Proteomics Facility, IZKF Aachen, RWTH Aachen University, Aachen, Germany.
⁶ Institute of Biochemistry and Molecular Immunology, Medical School, RWTH Aachen University, Aachen, Germany.
⁷ Institute for Drug Research, The Hebrew University of Jerusalem, Jerusalem, Israel. [email protected].

Abstract

The integrated stress response (ISR) converges on eIF2α phosphorylation to regulate protein synthesis. ISR is activated by several stress conditions, including endoplasmic reticulum (ER) stress, executed by protein kinase R-like endoplasmic reticulum kinase (PERK). We report that ER stress combined with ISR inhibition causes an impaired maturation of several tyrosine kinase receptors (RTKs), consistent with a partial block of their trafficking from the ER to the Golgi. Other proteins mature or are secreted normally, indicating selective retention in the ER (sERr). sERr is relieved upon protein synthesis attenuation and is accompanied by the generation of large mixed disulfide bonded complexes, including ERp44. sERr was pharmacologically recapitulated by combining the HIV-protease inhibitor nelfinavir with ISRIB, an experimental drug that inhibits ISR. Nelfinavir/ISRIB combination is highly effective to inhibit the growth of RTK-addicted cell lines and hepatocellular (HCC) cells in vitro and in vivo. Thus, pharmacological sERr can be utilized as a modality for cancer treatment.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetamides / pharmacology
Acetamides / therapeutic use
Animals
Antineoplastic Combined Chemotherapy Protocols / pharmacology*
Antineoplastic Combined Chemotherapy Protocols / therapeutic use
CRISPR-Cas Systems / genetics
Carcinoma, Hepatocellular / drug therapy*
Carcinoma, Hepatocellular / pathology
Cell Line, Tumor
Cyclohexylamines / pharmacology
Cyclohexylamines / therapeutic use
Endoplasmic Reticulum / drug effects*
Endoplasmic Reticulum / metabolism
Endoplasmic Reticulum Stress / drug effects
Gene Knockout Techniques
Golgi Apparatus / metabolism
Humans
Liver Neoplasms / drug therapy*
Liver Neoplasms / pathology
Male
Membrane Proteins / genetics
Membrane Proteins / metabolism
Mice
Molecular Chaperones / genetics
Molecular Chaperones / metabolism
Nelfinavir / pharmacology
Nelfinavir / therapeutic use
Xenograft Model Antitumor Assays
eIF-2 Kinase / genetics
eIF-2 Kinase / metabolism*

Substances

2-(4-chlorophenoxy)-N-(4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)acetamide
Acetamides
Cyclohexylamines
ERP44 protein, human
Membrane Proteins
Molecular Chaperones
EIF2AK3 protein, human
eIF-2 Kinase
Nelfinavir