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.
Highlights
The integrated stress response (ISR) converges on eIF2α phosphorylation to regulate protein synthesis
To explore whether protein kinase R-like endoplasmic reticulum kinase (PERK) inhibition is connected to P-Tyr homeostasis, Mel[526] cells were treated with the endoplasmic reticulum (ER) stress inducer thapsigargin (Tg), the PERK inhibitor GSK414, ISRIB, or combinations of Tg and GSK414 or ISRIB
PTyr levels were strongly reduced only following combined treatments (Fig. 1a, b). These data indicate that unfolded protein response (UPR)/ISR responses buffer P-Tyr levels in response to ER stress
Summary
The integrated stress response (ISR) converges on eIF2α phosphorylation to regulate protein synthesis. The phosphorylation of eIF2α attenuates global protein translation by sequestering the multisubunit GEF eIF2B, which is needed to charge the preinitiation complex with GTP This phosphorylation leads to preferred translation of selective mRNAs, such as the one encoding the transcription factor ATF41 that activates a transcription program controlling cell survival and cellular metabolism. A personalized approach for PERK inhibitors in cancer was proposed in light of strong pharmacological evidence that PERK inhibitors as single agents have profound anticancer efficacy against the BRAFV600Edependent tumors[9] Prompted by this discovery we analyzed BRAF mutated Mel[526] cells for total phospho-tyrosine (P-Tyr) levels under conditions of ER stress in the presence and absence of PERK inhibition
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