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 and Boaz Tirosh ()
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Mohamed Mahameed: The Hebrew University of Jerusalem
Shatha Boukeileh: The Hebrew University of Jerusalem
Akram Obiedat: The Hebrew University of Jerusalem
Odai Darawshi: The Hebrew University of Jerusalem
Priya Dipta: The Hebrew University of Jerusalem
Amit Rimon: The Hebrew University of Jerusalem
Gordon McLennan: Lerner Research Institute, Cleveland Clinic Foundation
Rosi Fassler: The Hebrew University of Jerusalem
Dana Reichmann: The Hebrew University of Jerusalem
Rotem Karni: IMRIC, The Hebrew University of Jerusalem
Christian Preisinger: IZKF Aachen, RWTH Aachen University
Thomas Wilhelm: RWTH Aachen University
Michael Huber: RWTH Aachen University
Boaz Tirosh: The Hebrew University of Jerusalem

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-15067-5

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