Inhibition of PERK-dependent pro-adaptive signaling pathway as a promising approach for cancer treatment
Journal Title: Polish Journal of Surgery - Year 2017, Vol 89, Issue 3
Abstract
Endoplasmic Reticulum (ER) is an organelle that is vital for cell growth and maintenance of homeostasis. Recent studies have reported that numerous human diseases, including cancer, are strictly connected to disruption of ER homeostasis. In order to counteract adverse intracellular conditions, cancer cells induce protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK)-dependent, pro-adaptive unfolded protein response (UPR) signaling branches. If ER stress is severe or prolonged, pro-adaptive signaling networks are insufficient, resulting in apoptotic cell death of cancer cells. The main aim: of the study was to evaluate the biological activity of a small-molecule PERK inhibitor GSK2606414 in two cancer cell lines - human neuroblastoma (SH-SY5Y) and human colorectal adenocarcinoma (HT-29) cell lines. We analyzed the level of phosphorylation of the eukaryotic initiation factor 2 (eIF2), which is the main substrate of PERK and a subsequent activator of UPR, which under long-term ER stress may evoke apoptotic death of cancer cells. Material and methods: In the study, we utilized commercially available cell lines of human colorectal adenocarcinoma HT-29 and human neuroblastoma SH-SY5Y. Cells were exposed to the tested PERK-dependent signaling inhibitor GSK2606414 in suitable culture media with addition of thapsigargin (500 nM) to induce ER stress. To identify the protein, Western blot with specific antibodies was used. Detection of immune complexes was performed using chemiluminescence. Results: We found a complete inhibition of p-eIF2α expression due to the GSK2606414 inhibitor in both cell lines, SH-SY5Y and HT-29. Conclusions: Currently available cancer treatments are insufficient and cause various side effects. It has been assumed that utilization of small-molecule inhibitors of the PERK-dependent signaling pathway, like GSK2606414, may switch the pro-adaptive branch of UPR to its pro-apoptotic branch. It is believed that the tested inhibitor GSK2606414 may become a promising treatment for many cancer types.<br/><br/>
Authors and Affiliations
Wioletta Rozpędek, Dariusz Pytel, Łukasz Dziki, Alicja Nowak, Adam Dziki, J. Alan Diehl, Ireneusz Majsterek
Keywords
Related Articles
- EP ID EP189645
- DOI 10.5604/01.3001.0010.1020
- Views 74
- Downloads 0
Sclerotherapy of esophageal varices in hemophilia patients with liver cirrhosis – a prospective, controlled clinical study
Introduction: Bleeding from esophageal varices is a serious clinical condition in hemophilia patients due to congenital deficiency or lack of clotting factors VIII (in hemophilia A) and IX (in hemophilia B), decreased cl...
New Method of Forced Implantation of Permanent Catheters for Hemodialysis into Critically Stenosed or Occluded Central Veins
The aim of the study was to report a novel technique of forced implantation of catheters for hemodialysis into critically stenosed or occluded central veins, without preceding angioplasty or stenting. Material and method...
Surgical Cost of Care in Crohn’s Disease
The aim of the study was to evaluate the cost of surgical care and short-term outcomes of Crohn’s disease(CD) in the era of laparoscopy and biologic therapy. Material and methods. Review of a prospective database identif...
Wzmocnienie zespolenia wątrobowo-jelitowego więzadłem obłym wątroby może być korzystne
Wstęp: Wyciek żółci i zwężenie stanowią poważne powikłania zespolenia wątrobowo-jelitowego (hepaticojejunostomy; HJ). Dane wskazują, że użycie więzadła obłego wątroby (ligamentum teres hepatis; LTH) do wzmocnienia HJ moż...
Assessment of pharmacological prophylaxis for acute pancreatitis following ERCP in patients with choledoholithi
Endoscopic retrograde cholangiopancreatography (ERCP) is an effective tool in the diagnostics and treatment of bile duct diseases. Although minimally invasive, the procedure is associated with a risk of complications, wi...