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Use of Small-molecule Inhibitory Compound of PERK-dependent Signaling Pathway as a Promising Target-based Therapy for Colorectal Cancer

[ Vol. 20 , Issue. 3 ]

Author(s):

Wioletta Rozpędek, Dariusz Pytel, Adam Wawrzynkiewicz, Natalia Siwecka, Adam Dziki, Łukasz Dziki, J. Alan Diehl and Ireneusz Majsterek*Pages 223-238 (16)

Abstract:


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.

Keywords:

PERK, eIF2α, PERK inhibitor, endoplasmic reticulum stress, unfolded protein response, cancer, apoptosis.

Affiliation:

Department of Clinical Chemistry and Biochemistry, Medical University of Lodz, Lodz, Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, Department of Clinical Chemistry and Biochemistry, Medical University of Lodz, Lodz, Department of Clinical Chemistry and Biochemistry, Medical University of Lodz, Lodz, Department of General and Colorectal Surgery, Medical University of Lodz, Lodz, Department of General and Colorectal Surgery, Medical University of Lodz, Lodz, Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, Department of Clinical Chemistry and Biochemistry, Medical University of Lodz, Lodz

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