Pytel Dariusz, Gao Yan, Mackiewicz Katarzyna, Katlinskaya Yuliya V, Staschke Kirk A, Paredes Maria C G, Yoshida Akihiro, Qie Shuo, Zhang Gao, Chajewski Olga S, Wu Lawrence, Majsterek Ireneusz, Herlyn Meenhard, Fuchs Serge Y, Diehl J Alan
Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina, United States of America.
Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
PLoS Genet. 2016 Dec 15;12(12):e1006518. doi: 10.1371/journal.pgen.1006518. eCollection 2016 Dec.
The unfolded protein response (UPR) regulates cell fate following exposure of cells to endoplasmic reticulum stresses. PERK, a UPR protein kinase, regulates protein synthesis and while linked with cell survival, exhibits activities associated with both tumor progression and tumor suppression. For example, while cells lacking PERK are sensitive to UPR-dependent cell death, acute activation of PERK triggers both apoptosis and cell cycle arrest, which would be expected to contribute tumor suppressive activity. We have evaluated these activities in the BRAF-dependent melanoma and provide evidence revealing a complex role for PERK in melanoma where a 50% reduction is permissive for BrafV600E-dependent transformation, while complete inhibition is tumor suppressive. Consistently, PERK mutants identified in human melanoma are hypomorphic with dominant inhibitory function. Strikingly, we demonstrate that small molecule PERK inhibitors exhibit single agent efficacy against BrafV600E-dependent tumors highlighting the clinical value of targeting PERK.
未折叠蛋白反应（UPR）在细胞暴露于内质网应激后调节细胞命运。PERK是一种UPR蛋白激酶，调节蛋白质合成，虽然与细胞存活相关，但表现出与肿瘤进展和肿瘤抑制相关的活性。例如，虽然缺乏PERK的细胞对依赖UPR的细胞死亡敏感，但PERK的急性激活会触发细胞凋亡和细胞周期停滞，这有望促进肿瘤抑制活性。我们在BRAF依赖性黑色素瘤中评估了这些活性，并提供证据揭示了PERK在黑色素瘤中的复杂作用，其中PERK减少50%允许BrafV600E依赖性转化，而完全抑制则具有肿瘤抑制作用。一致地，在人类黑色素瘤中鉴定出的PERK突变体是具有显性抑制功能的亚型。引人注目的是，我们证明小分子PERK抑制剂对BrafV600E依赖性肿瘤具有单药疗效，突出了靶向PERK的临床价值。
