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CDH1 overexpression sensitizes TRAIL resistant breast cancer cells towards rhTRAIL induced apoptosis

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Abstract

Purpose

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is well known for its unique ability to induce apoptosis in cancer cells but not normal cells. However, a subpopulation of cancer cells exist that does not respond to toxic doses of TRAIL. In this study, we aimed to identify key factors regulating TRAIL resistance in breast cancer.

Methods

rhTRAIL (recombinant human TRAIL) resistant cells (TR) isolated from TRAIL sensitive MDA-MB-231 parental cells (TS) were confirmed using trypan blue assay, cell viability assay and AO/EtBr (acridine orange/ethidium bromide) staining. Microarray was performed followed by analysis using DAVID and Cytoscape bioinformatics software to identify the candidate hub gene. Gene expression of the candidate gene was confirmed using real-time PCR and western blot. Candidate gene was overexpressed via transient transfection to identify its significance in the context of rhTRAIL. Breast cancer patient data was obtained from The Cancer Genome Atlas (TCGA) database.

Results

Whole transcriptome analysis identified 4907 differentially expressed genes (DEGs) between TS and TR cells. CDH1 was identified as the candidate hub gene, with 18-degree centrality. We further observed CDH1 protein to be downregulated, overexpression of which increased apoptosis in TR cells after rhTRAIL treatment. TCGA patient data analysis also showed CDH1 mRNA to be low in TRAIL resistant patient group compared to TRAIL sensitive group.

Conclusion

CDH1 overexpression sensitizes TR cells towards rhTRAIL induced apoptosis. Therefore, we can hypothesize that CDH1 expression should be taken into account while performing TRAIL therapy in breast cancer.

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Availability of data and material

The microarray data that supports the findings of this study are available from the corresponding author, RP, upon reasonable request.

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Acknowledgements

This work was supported by the Department of Science and Technology - Science and Engineering Research Board (DST-SERB) under grant number EMR/2014/001009 to Dr. Ranjana Pal and Dr. Nabendu Biswas. P.T., A.P. and N.G. were supported by fellowship from Department of Science and Technology - Innovation in Science Pursuit for Inspired Research (DST-INSPIRE), Department of Science and Technology - Science and Engineering Research Board (DST-SERB) and Council of Scientific & Industrial Research - National Eligibility Test (CSIR-NET) fellowship, respectively. Infrastructure support was made possible with funds from the Presidency University, Department of Biotechnology - Boost to University Interdisciplinary Life Science Departments for Education and Research programme (DBT-BUILDER) and Department of Science and Technology - Fund for Improvement of S&T Infrastructure (DST-FIST)

Funding

This work was supported by the Department of Science and Technology - Science and Engineering Research Board (DST-SERB) under grant number EMR/2014/001009 to Dr. Ranjana Pal and Dr. Nabendu Biswas. P.T., A.P. and N.G. were supported by fellowship from Department of Science and Technology - Innovation in Science Pursuit for Inspired Research (DST-INSPIRE), Department of Science and Technology - Science and Engineering Research Board (DST-SERB) and Council of Scientific & Industrial Research - National Eligibility Test (CSIR-NET) fellowship, respectively. Infrastructure support was made possible with funds from the Presidency University, Department of Biotechnology - Boost to University Interdisciplinary Life Science Departments for Education and Research programme (DBT-BUILDER) and Department of Science and Technology - Fund for Improvement of S&T Infrastructure (DST-FIST).

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Authors and Affiliations

  1. Department of Life Sciences, Presidency University, 86/1 College Street, Kolkata, West Bengal, 700073, India

    Poulami Tapadar, Ambika Pal, Nirajan Ghosal, Tamalika Paul, Nabendu Biswas & Ranjana Pal

  2. Department of Biochemistry, Institute of Home Economics, University of Delhi, New Delhi, 110016, India

    Bhupender Kumar

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  1. Poulami Tapadar
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  2. Ambika Pal
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  3. Nirajan Ghosal
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Contributions

Conceived and designed the experiments: RP, NB. Performed the experiments: PT AP NG TP. Analyzed the data: PT RP NB. Analyzed TCGA data: PT RP BK. Wrote the paper: PT RP.

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Correspondence to Ranjana Pal.

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Tapadar, P., Pal, A., Ghosal, N. et al. CDH1 overexpression sensitizes TRAIL resistant breast cancer cells towards rhTRAIL induced apoptosis. Mol Biol Rep 50, 7283–7294 (2023). https://doi.org/10.1007/s11033-023-08657-1

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