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Targeting STAT proteins via computational analysis in colorectal cancer
Begum Dariya1, Santoshi Muppala2, Gowru Srivani1
1Department of Bioscience and Biotechnology, Banasthali University, Vanasthali, Rajasthan, 304022, India.
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.
Insights
Genistein effectively inhibits colorectal cancer (CRC) by interacting with signal transducer and activator of transcription (STAT) proteins, particularly STAT3. This research highlights genistein as a potential therapeutic agent for CRC treatment.
Area of Science:
- Oncology
- Molecular Biology
- Computational Chemistry
Background:
- Colorectal cancer (CRC) is a major global health concern, often driven by dysregulated signal transducer and activator of transcription (STAT) proteins within the JAK-STAT pathway.
- STAT proteins (STAT1, STAT2, STAT3) are implicated in cancer pathogenesis and represent key therapeutic targets.
Purpose of the Study:
- To computationally investigate the molecular interactions between genistein, a chemopreventive phytochemical, and STAT1, STAT2, and STAT3 proteins.
- To evaluate the potential of genistein as an inhibitor of STAT proteins in the context of colorectal cancer progression.
Main Methods:
- Molecular docking simulations were performed to assess the binding affinity of genistein to STAT1, STAT2, and STAT3.
- Molecular dynamic simulations were conducted specifically for the STAT2 protein.
- In vitro experiments involved treating CRC cell lines (HCT 116 and HT-29) with genistein.
Main Results:
- Molecular docking predicted effective interactions and favorable binding energies between genistein and STAT proteins.
- Genistein treatment significantly suppressed cell proliferation in CRC cell lines.
- Genistein significantly reduced STAT3 protein expression in CRC cell lines.
Conclusions:
- Genistein demonstrates potent inhibitory effects against colorectal cancer, likely through its interaction with STAT proteins, especially STAT3.
- Targeting STAT3 with genistein shows promise for developing novel, effective colorectal cancer therapies with improved potency and bioavailability.
