Use of Small-molecule Inhibitory Compound of PERK-dependent Signaling Pathway as a Promising Target-based Therapy for Colorectal Cancer.
BACKGROUND
Colorectal cancer constitutes one of the most common cancer with a high mortality rate. The newest data has reported that activation of the pro-apoptotic PERK-dependent unfolded protein response signaling pathway by small-molecule inhibitors may constitute an innovative anti-cancer treatment strategy.


OBJECTIVE
In the presented study, we evaluated the effectiveness of the PERK-dependent unfolded protein response signaling pathway small-molecule inhibitor 42215 both on HT-29 human colon adenocarcinoma and CCD 841 CoN normal human colon epithelial cell lines.


METHODS
Cytotoxicity of the PERK inhibitor was evaluated by the resazurin-based and lactate dehydrogenase (LDH) tests. Apoptotic cell death was measured by flow cytometry using the FITCconjugated Annexin V to indicate apoptosis and propidium iodide to indicate necrosis as well as by colorimetric caspase-3 assay. The effect of tested PERK inhibitor on cell cycle progression was measured by flow cytometry using the propidium iodide staining. The level of the phosphorylated form of the eukaryotic initiation factor 2 alpha was detected by the Western blot technique.


RESULTS
Obtained results showed that investigated PERK inhibitor is selective only toward cancer cells, since inhibited their viability in a dose- and time-dependent manner and induced their apoptosis and G2/M cell cycle arrest. Furthermore, 42215 PERK inhibitor evoked significant inhibition of eIF2α phosphorylation within HT-29 cancer cells.


CONCLUSION
Highly-selective PERK inhibitors may provide a ground-breaking, anti-cancer treatment strategy via activation of the pro-apoptotic branch of the PERK-dependent unfolded protein response signaling pathway.
['Rozpędek|Wioletta|W|', 'Pytel|Dariusz|D|', 'Wawrzynkiewicz|Adam|A|', 'Siwecka|Natalia|N|', 'Dziki|Adam|A|', 'Dziki|Łukasz|Ł|', 'Diehl|J Alan|JA|', 'Majsterek|Ireneusz|I|']
D000230:Adenocarcinoma D000970:Antineoplastic Agents D017209:Apoptosis D002453:Cell Cycle D049109:Cell Proliferation D015179:Colorectal Neoplasms D015852:Eukaryotic Initiation Factor-2 D006801:Humans D010766:Phosphorylation D054852:Small Molecule Libraries D014407:Tumor Cells, Cultured D019892:eIF-2 Kinase
cancer PERK PERK inhibitor apoptosis eIF2α endoplasmic reticulum stress unfolded protein response.