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Targeting STAT proteins via computational analysis in colorectal cancer

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Abstract

Colorectal cancer (CRC) is the third most common cancer diagnosed worldwide making it a serious global challenge. CRC progression results from dysregulated cytoplasmic transcription factors, including signal transducer and activator of transcription (STAT) proteins that are involved in JAK-STAT pathway. The STAT proteins contain a conserved SH2 domain that facilitates the initiation of STAT activation via binding to tyrosine motifs followed by STAT dimerization. The STAT proteins include STAT1, STAT2 and STAT3 which all facilitate therapeutic targets for many drugs, since they are associated with pathogenesis in various cancers such as CRC. Genistein is an efficient chemopreventive phytochemical drug against CRC. The current investigation presents a computational study performed to investigate the molecular interaction between STAT1, STAT2 and STAT3 proteins with genistein. The molecular dynamic simulation was conducted for STAT2 protein. The studies from molecular docking revealed that the interaction of STAT proteins and genistein is predicted to be effective with better binding energies. Furthermore, targeting STAT3 could be an efficient therapeutic target and understanding the interaction between STAT3 and genistein can help to contribute to a better inhibition process for CRC progression. Treatment with genistein led to significant suppression of cell proliferation and STAT3 protein expression in both CRC (HCT 116 and HT-29) cell lines. This further provides development of efficient STAT inhibitors with better potency and bioavailability.

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Abbreviations

CRC:

Colorectal cancer

MDS:

Molecular dynamic simulation

MM:

Molecular mechanics

NMR:

Nuclear magnetic resonance

PDB:

Protein data bank

RMSD:

Root mean square deviation

RMSF:

Root mean square fluctuation

STAT:

Signal transducer and activator of transcription

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Authors and Affiliations

  1. Department of Bioscience and Biotechnology, Banasthali University, Vanasthali, Rajasthan, 304022, India

    Begum Dariya, Gowru Srivani & Afroz Alam

  2. Department of Cardiovascular & Metabolic Sciences, Cleveland Clinic, Cleveland, OH, USA

    Santoshi Muppala

  3. Department of Biology, Emory University, Atlanta, GA, 30322, USA

    Saimila Momin

  4. School of Medicine, University of Missouri-Columbia, Columbia, MO, 65212, USA

    Madhu Sudhana Saddala

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  1. Begum Dariya
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Dariya, B., Muppala, S., Srivani, G. et al. Targeting STAT proteins via computational analysis in colorectal cancer. Mol Cell Biochem 476, 165–174 (2021). https://doi.org/10.1007/s11010-020-03893-6

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