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

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.

• Authors: 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
• Journal: Nature communications (Nat Commun) Vol. 11 Issue 1 Pg. 1304 (03 11 2020) ISSN: 2041-1723 [Electronic] England
• PMID: 32161259 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

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