Claudin-1 interacts with EPHA2 to promote cancer stemness and chemoresistance in colorectal cancer

Mark Primeaux; Xiangdong Liu; Saiprasad Gowrikumar; Iram Fatima; Kurt W Fisher; Dhundy Bastola; Alex J Vecchio; Amar B Singh; Punita Dhawan

doi:10.1016/j.canlet.2023.216479

Claudin-1 interacts with EPHA2 to promote cancer stemness and chemoresistance in colorectal cancer

Cancer Lett. 2023 Nov 28:579:216479. doi: 10.1016/j.canlet.2023.216479. Epub 2023 Nov 2.

Authors

Mark Primeaux¹, Xiangdong Liu², Saiprasad Gowrikumar¹, Iram Fatima¹, Kurt W Fisher³, Dhundy Bastola⁴, Alex J Vecchio², Amar B Singh⁵, Punita Dhawan⁶

Affiliations

¹ Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.
² Department of Biochemistry, University of Nebraska-Lincoln, Lincoln, NE, USA.
³ Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA.
⁴ Department of Bioinformatics, University of Nebraska Omaha, Omaha, NE, USA.
⁵ Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA; Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA; VA Nebraska-Western Iowa Health Care System, Omaha, NE, USA.
⁶ Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA; Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA; VA Nebraska-Western Iowa Health Care System, Omaha, NE, USA. Electronic address: punita.dhawan@unmc.edu.

PMID: 37924938
PMCID: PMC10765961 (available on 2024-11-28)
DOI: 10.1016/j.canlet.2023.216479

Abstract

Therapy resistance is the primary problem in treating late-stage colorectal cancer (CRC). Claudins are frequently dysregulated in cancer, and several are being investigated as novel therapeutic targets and biomarkers. We have previously demonstrated that Claudin-1 (CLDN1) expression in CRC promotes epithelial-mesenchymal transition, metastasis, and resistance to anoikis. Here, we hypothesize that CLDN1 promotes cancer stemness and chemoresistance in CRC. We found that high CLDN1 expression in CRC is associated with cancer stemness and chemoresistance signaling pathways in patient datasets, and it promotes chemoresistance both in vitro and in vivo. Using functional stemness assays, proteomics, biophysical binding assays, and patient-derived organoids, we found that CLDN1 promotes properties of cancer stemness including CD44 expression, tumor-initiating potential, and chemoresistance through a direct interaction with ephrin type-A receptor 2 (EPHA2) tyrosine kinase. This interaction is dependent on the CLDN1 PDZ-binding motif, increases EPHA2 protein expression by inhibiting its degradation, and enhances downstream AKT signaling and CD44 expression to promote stemness and chemoresistance. These results suggest CLDN1 is a viable target for pharmacological intervention and/or biomarker development.

Keywords: Cancer stemness; Chemoresistance; Claudin-1; Colorectal cancer; EPHA2.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Cell Line, Tumor
Claudin-1 / genetics
Claudin-1 / metabolism
Colorectal Neoplasms* / drug therapy
Colorectal Neoplasms* / genetics
Colorectal Neoplasms* / pathology
Drug Resistance, Neoplasm
Gene Expression Regulation, Neoplastic
Humans
Signal Transduction

Substances

Claudin-1
CLDN1 protein, human
EPHA2 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding