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

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

17 Scopus citations

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.

Original language	English
Article number	1304
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-15067-5
State	Published - 1 Dec 2020

Bibliographical note

Funding Information:
B.T. is the incumbent of the David Eisenberg Chair in Pharmacy. Research was funded by grants from the David R. Bloom Center for Pharmacy, the Dr. Adolph and Klara Brettler Center for Research in Pharmacology, Israel Cancer Association Grant No. 20200018 (B.T.), ISF Grants Nos. 696/2014 (B.T.), 1537/18, 1765/13 (D.R.), Treatment H2020-MSCA-ITN-721236 (B.T. and P.D.), START Program of the Medical Faculty of the RWTH Aachen University (T.W., 691517), German Israeli Fund (Grant no. I-1471-414.13/2018) to B.T. and M.H. M.M. is the recipient of the Zvi Yanai Doctoral Fellowship of the Israeli Ministry of Science and Technology.

Publisher Copyright:
© 2020, The Author(s).

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Mahameed, M., Boukeileh, S., Obiedat, A., Darawshi, O., Dipta, P., Rimon, A., McLennan, G., Fassler, R., Reichmann, D., Karni, R., Preisinger, C., Wilhelm, T., Huber, M., & Tirosh, B. (2020). Pharmacological induction of selective endoplasmic reticulum retention as a strategy for cancer therapy. Nature Communications, 11(1), Article 1304. https://doi.org/10.1038/s41467-020-15067-5

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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.",

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

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