PERK Is a Haploinsufficient Tumor Suppressor: Gene Dose Determines Tumor-Suppressive Versus Tumor Promoting Properties of PERK in Melanoma

Pytel, Dariusz; Gao, Yan; Mackiewicz, Katarzyna; Katlinskaya, Yuliya; Staschke, Kirk A.; Paredes, Maria Cristina Garcia; Yoshida, Akihiro; Qie, Shuo; Zhang, Gao; Chajewski, Olga S.; Wu, Lawrence W.; Majsterek, Ireneusz; Herlyn, Meenhard; Fuchs, Serge Y.; Diehl, J. Alan

doi:10.1371/journal.pgen.1006518

Cited by 49 publications

(40 citation statements)

References 82 publications

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“…PERK mutants identified in human melanoma are hypomorphic with dominant inhibitory function. 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 Mel526 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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confidence: 99%

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

et al. 2020

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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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confidence: 99%

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

et al. 2020

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“…For instance, PERK is activated and is required for Mycdependent transformation [39] and the development of resistance to chemotherapy [40]. In melanoma, particularly in the BRAF mutated tumors, PERK is particularly important and serves oncogenic properties indicating its constitutive activation [41]. Here, we present a new function of the PERK pathway that can be exploited for improved immunotherapy.…”

Section: Discussionmentioning

confidence: 97%

The integrated stress response promotes B7H6 expression

et al. 2019

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The B7 family member, B7H6, is a ligand for the natural killer cell receptor NKp30. B7H6 is hardly expressed on normal tissues, but undergoes upregulation on different types of tumors, implicating it as an attractive target for cancer immunotherapy. The molecular mechanisms that control B7H6 expression are poorly understood. We report that in contrast to other NK cell ligands, endoplasmic reticulum (ER) stress upregulates B7H6 mRNA levels and surface expression. B7H6 induction by ER stress requires protein kinase R-like ER kinase (PERK), one of the three canonical sensors of the unfolded protein response. PERK phosphorylates eIF2α, which regulates protein synthesis and gene expression. Because eIF2α is phosphorylated by several kinases following different stress conditions, the program downstream to eIF2α phosphorylation is called the integrated stress response (ISR). Several drugs were reported to promote the ISR. Nelfinavir and lopinavir, two clinically approved HIV protease inhibitors, promote eIF2α phosphorylation by different mechanisms. We show that nelfinavir and lopinavir sustainably instigate B7H6 expression at their pharmacologically relevant concentrations. As such, ER stress and ISR conditions sensitize melanoma targets to CART cells directed against B7H6. Our study highlights a novel mechanism to induce B7H6 expression and suggests a pharmacological approach to improve B7H6-directed immunotherapy.

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“…These results indicate that PERK functions to support the dissemination of the leukemic cells and, accordingly, might play an important role in progression of Myc-driven leukemias. Thus, it can be argued that pharmacologic inhibitors of PERK proposed to be used against solid tumors (11,24) might not be very efficient in helping to eradicate the Myc-induced leukemias but could be useful in slowing down the progression of the disease.…”

Section: Discussionmentioning

confidence: 99%

“…PERK is induced during tumor development and progression in response to the stress stimuli originating from activation oncogenes (such as c-Myc) or/and deficit of glucose and oxygen in the tumor microenvironment (1). Whereas tempered PERK activities (due to hypomorphic mutants or haploinsufficiency) may promote initiation of melanomas (24), the complete ablation or inhibition of PERK is incompatible with solid tumor growth (4,(24)(25)(26)(27). These findings prompted academic and industrial efforts to develop potent and selective inhibitors of PERK (28).…”

Section: Introductionmentioning

confidence: 99%

The PKR-Like Endoplasmic Reticulum Kinase Promotes the Dissemination of Myc-Induced Leukemic Cells

Gui

Katlinski

Koumenis

et al. 2019

Molecular Cancer Research

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Hyperactive oncogenic Myc stimulates protein synthesis that induces the unfolded protein response, which requires the function of the eukaryotic translation initiation factor 2-alpha kinase 3, also known as protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK). Activated PERK acts to limit mRNA translation, enable proper protein folding, and restore the homeostasis in the endoplasmic reticulum. Given that Myc activation contributes to many types of lymphoid and myeloid human leukemias, we used a mouse model to examine the importance of PERK in development and progression of Mycinduced leukemias. We found that genetic ablation of Perk does not suppress the generation of the leukemic cells in the bone marrow. However, the cell-autonomous Perk deficiency restricts the dissemination of leukemic cells into peripheral blood, lymph nodes, and vital peripheral organs. Whereas the loss of the IFNAR1 chain of type I IFN receptor stimulated leukemia, Perk ablation did not stabilize IFNAR1, suggesting that PERK stimulates the leukemic cells' dissemination in an IFNAR1-independent manner. We discuss the rationale for using PERK inhibitors against Myc-driven leukemias. Implications: The role of PERK in dissemination of Myc-induced leukemic cells demonstrated in this study argues for the use of PERK inhibitors against leukemia progression.

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PERK Is a Haploinsufficient Tumor Suppressor: Gene Dose Determines Tumor-Suppressive Versus Tumor Promoting Properties of PERK in Melanoma

Cited by 49 publications

References 82 publications

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

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

The integrated stress response promotes B7H6 expression

The PKR-Like Endoplasmic Reticulum Kinase Promotes the Dissemination of Myc-Induced Leukemic Cells

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