Targeting STAT proteins via computational analysis in colorectal cancer
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Targeting STAT proteins via computational analysis in colorectal cancer Begum Dariya1 · Santoshi Muppala2 · Gowru Srivani1 · Saimila Momin3 · Afroz Alam1 · Madhu Sudhana Saddala4 Received: 29 June 2020 / Accepted: 17 August 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
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. Keywords Colorectal cancer · STAT · Genistein · Transcription factor · Phytochemical 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
* Madhu Sudhana Saddala [email protected] 1
Department of Bioscience and Biotechnology, Banasthali University, Vanasthali, Rajasthan 304022, India
2
Department of Cardiovascular & Metabolic Sciences, Cleveland Clinic, Cleveland, OH, USA
3
Department of Biology, Emory University, Atlanta, GA 30322, USA
4
School of Medicine, University of Missouri-Columbia, Columbia, MO 65212, USA
Introduction Colorectal cancer (CRC) incidence has been increasing rapidly and remains as the third most common cause for mortality around the world [1, 2]. Risk factors include dietary habits, obesity, smoking, etc. [3]. The best treatment options have yet to come despite many years of research. Currently the only advanced treatment options that are available are radio and chemotherapy. And most of these therapies fail d
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