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Use of Small-molecule Inhibitory Compound of PERK-dependent Signaling Pathway as a Promising Target-based Therapy for
Wioletta Rozpędek1, Dariusz Pytel2, Adam Wawrzynkiewicz1
1Department of Clinical Chemistry and Biochemistry, Medical University of Lodz, Lodz, Poland.
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.
Insights
A novel PERK inhibitor selectively targets colorectal cancer cells, inducing apoptosis and cell cycle arrest. This discovery offers a promising new strategy for cancer treatment by activating the unfolded protein response pathway.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Colorectal cancer is a leading cause of cancer mortality.
- Targeting the PERK-dependent unfolded protein response pathway with small-molecule inhibitors presents a novel anti-cancer strategy.
Purpose of the Study:
- To evaluate the effectiveness of the PERK inhibitor 42215 on HT-29 human colon adenocarcinoma and CCD 841 CoN normal human colon epithelial cells.
- To assess the selectivity of the PERK inhibitor against cancer cells.
Main Methods:
- Cytotoxicity assessed via resazurin and lactate dehydrogenase (LDH) assays.
- Apoptosis and necrosis measured by Annexin V/propidium iodide staining and caspase-3 assay.
- Cell cycle progression analyzed by propidium iodide staining and eIF2α phosphorylation by Western blot.
Main Results:
- The PERK inhibitor 42215 demonstrated dose- and time-dependent inhibition of HT-29 cancer cell viability.
- The inhibitor induced apoptosis and G2/M cell cycle arrest specifically in cancer cells.
- Significant inhibition of eIF2α phosphorylation was observed in HT-29 cells.
Conclusions:
- Highly selective PERK inhibitors represent a groundbreaking anti-cancer treatment strategy.
- Activation of the pro-apoptotic branch of the PERK-dependent unfolded protein response pathway is key.
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