Reduction of Chemoresistance by Claudin-14-Targeting Peptide in Human Colorectal Cancer Cells
Yuko Mizukami1, Shotaro Hashimoto1, Tomoka Ando1
1Department of Biopharmaceutical Sciences, Laboratory of Biochemistry, Gifu Pharmaceutical University, Gifu, Japan.
Abstract:
The expression of claudins (CLDNs), major components of tight junctions (TJs), is abnormal in various solid tumors. CLDN14 is highly expressed in human colorectal cancer (CRC) tissues and confers chemoresistance. CLDN14 may become a novel therapeutic target for CRC, but CLDN14-targeting drugs have not been developed. Here, we searched for a CLDN14-targeting peptide, which can suppress CLDN14 expression and chemoresistance using human CRC-derived DLD-1 and LoVo cells. Among some short peptides which mimic the second extracellular loop structure of CLDN14, PSGMK most strongly suppressed the protein expression of CLDN14. The mRNA expression of other endogenous TJ components was unchanged by PSGMK. The PSGMK-induced reduction of CLDN14 protein was inhibited by chloroquine, a lysosome inhibitor, and monodansylcadaverine, a clathrin-dependent endocytosis inhibitor, indicating that PSGMK may enhance endocytosis and lysosomal degradation of CLDN14. In a three-dimensional culture model, the oxidative stress was significantly reduced by PSGMK, whereas hypoxia stress was not. Furthermore, the expression levels of nuclear factor erythroid 2-related factor 2, an oxidative stress response factor, and its target genes were decreased by PSGMK. These results suggest that PSGMK relieves stress conditions in spheroids. The cell viability of spheroids was decreased by anticancer drugs such as doxorubicin and oxaliplatin, which was exaggerated by the cotreatment with PSGMK. Our data indicate that CLDN14-targeting peptide, PSGMK has an anti-chemoresistance effect in CRC cells.
Insights
A novel peptide, PSGMK, targets Claudin 14 (CLDN14) in colorectal cancer (CRC), reducing chemoresistance. This CLDN14-targeting peptide enhances drug efficacy by suppressing CLDN14 expression and oxidative stress in CRC cells.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Claudins (CLDNs) are key tight junction proteins with altered expression in solid tumors.
- Claudin 14 (CLDN14) is overexpressed in colorectal cancer (CRC) and linked to chemoresistance.
- Developing CLDN14-targeting therapies for CRC is a significant unmet need.
Purpose of the Study:
- To identify a peptide that targets CLDN14 and suppresses its expression and associated chemoresistance in CRC.
- To investigate the mechanism of action of the identified peptide.
- To evaluate the peptide's efficacy in combination with chemotherapy in CRC models.
Main Methods:
- Screening of short peptides mimicking CLDN14's extracellular loop.
- Assessment of peptide effects on CLDN14 expression in DLD-1 and LoVo CRC cells.
- Investigation of peptide-induced degradation pathways using lysosome and endocytosis inhibitors.
- Evaluation of peptide effects on oxidative stress and chemoresistance in 3D CRC spheroid models.
Main Results:
- The peptide PSGMK significantly suppressed CLDN14 protein expression without affecting other tight junction components.
- PSGMK-induced CLDN14 reduction involved enhanced endocytosis and lysosomal degradation.
- PSGMK alleviated oxidative stress and reduced the expression of Nrf2 and its target genes in CRC spheroids.
- PSGMK potentiated the cytotoxic effects of doxorubicin and oxaliplatin in CRC spheroids.
Conclusions:
- The CLDN14-targeting peptide PSGMK demonstrates anti-chemoresistance properties in colorectal cancer.
- PSGMK offers a potential therapeutic strategy to overcome chemoresistance in CRC by targeting CLDN14.
- Further development of PSGMK could lead to novel treatments for colorectal cancer patients.
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