Inhibitors of Perk-dependent Signaling Pathway as a Promising Therapy for Cancer Treatment

Abstract: Currently, cancer constitutes a primary health problem worldwide, since elimination of cancer cells is still inadequate due to insufficient treatment strategy. The newest data has reported that PERK-dependent signaling branches have a significant impact on development and progression of many human diseases including cancer. Hypoxia is the major hallmark of tumour microenvironment, that is strictly associated with rapid cancer progression and induction of metastasis. Low oxygen tension within cancer cells may trigger aggregation of unfolded and misfolded protein within the Endoplasmic Reticulum (ER) lumen and subsequently evoke ER stress condition. As a response to Protein kinase RNA-like endoplasmic reticulum kinase (PERK) oligomerization and trans-autophosphorylation the Unfolded Protein Response (UPR) signaling pathways is activated and regulates their downstream effector such as Eukaryotic Initiation Factor 2 alpha (eIF2α). The eIF2α plays a key role in maintenance of cellular homeostasis via attenuation of global protein synthesis and expression of only selected pro-adaptive genes. Interestingly, UPR has a dual role, since under excessive, long-termed pathological conditions activated PERK contributes to increased translation of CCAAT-enhancer-binding protein homologous protein (CHOP), which may switch on the death signal within cells, that results in apoptotic death of cancer cells. The molecular mechanisms that switch the signal from pro-adaptive into pro-apoptotic is still unknown, but there is an ample of evidence, that utilization of small-molecule PERK inhibitors may lead to the activation of apoptotic cell death and provide an effective elimination of tumour cells. Thereby, potent, highly-selective inhibitors toward PERK may provide a ground-breaking, anti-cancer treatment strategy.

Adam Wawrzynkiewicz, Wioletta Rozpedek, Dariusz Pytel, Adam Dziki, Lukasz Dziki, Ireneusz Majsterek

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