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AKT inhibition sensitizes EVI1 expressing colon cancer cells to irinotecan therapy by regulating the Akt/mTOR axis

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Abstract

Purpose

Ecotropic viral integration site 1 (EVI1) is an oncogenic transcription factor that has been attributed to chemotherapy resistance in different cancers. As yet, however, its role in colon cancer drug resistance is not completely understood. Here, we set out to investigate the functional and therapeutic relevance of EVI1 in colon cancer drug resistance.

Methods

The EVI1 gene was knocked down in colon cancer cells that were subsequently tested for susceptibility to irinotecan using in vitro assays and in vivo subcutaneous mouse colon cancer models. The effect of EVI1 knockdown on the AKT-mTOR signaling pathway was assessed using cell line models, immunohistochemistry and bioinformatics tools. The anti-proliferative activity of AKT inhibitor GSK690693 and its combination with irinotecan was tested in colon cancer cell line models (2D and 3D). Finally, the therapeutic efficacy of GSK690693 and its combination with irinotecan was evaluated in xenografted EVI1 expressing colon cancer mouse models.

Results

We found that EVI1 knockdown decreased cancer stem cell-like properties and improved irinotecan responses in both cell line and subcutaneous mouse models. In addition, we found that EVI1 downregulation resulted in inhibition of AKT/mTOR signaling and RICTOR expression. Knocking down RICTOR expression increased the cytotoxic effects of irinotecan in EVI1 downregulated colon cancer cells. Co-treatment with irinotecan and ATP-competitive AKT inhibitor GSK690693 significantly reduced colon cancer cell survival and tumor progression rates.

Conclusion

Inhibition of the AKT signaling cascade by GSK690693 may serve as an alternative to improve the irinotecan response in EVI1-expressing colon cancer cells.

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Acknowledgments

P is supported by the National Post-Doctoral Fellowship (PDF/2018/000531), Science & Engineering Research Board, Department of Science and Technology, Government of India. VS is supported by the Council of Scientific and Industrial Research (CSIR), Government of India. The authors would like to acknowledge the help of Dr. Murali Dharan Bashyam and K. Viswakalyan from the Centre for DNA Fingerprinting and Diagnostics for providing the TMA slides.

Funding

The work was partly supported by intramural funding from the host institution and partly by a National Post-Doctoral Fellowship (PDF/2018/000531), Science & Engineering Research Board, Department of Science and Technology, Government of India.

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Authors and Affiliations

  1. Cancer Biology Group, Institute of Life Sciences, Nalco Square, Bhubaneswar, Odisha, 751023, India

    Pradeepa & Soumen Chakraborty

  2. Tumor Microenvironment and Animal Models Group, Institute of Life Sciences, Nalco Square, Bhubaneswar, 751023, India

    Voddu Suresh & Shantibhusan Senapati

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  1. Pradeepa
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  2. Voddu Suresh
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  4. Soumen Chakraborty
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Contributions

SC and P designed the experiments. P performed the in vitro studies, animal experiments and data acquisition. VS performed all the assays related to IHC. SBS did the IHC assays and scored the slides. P wrote the manuscript. SC reviewed and corrected the manuscript and arranged the funds. All authors approved the final version of the manuscript.

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Correspondence to Soumen Chakraborty.

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Pradeepa, Suresh, V., Senapati, S. et al. AKT inhibition sensitizes EVI1 expressing colon cancer cells to irinotecan therapy by regulating the Akt/mTOR axis. Cell Oncol. 45, 659–675 (2022). https://doi.org/10.1007/s13402-022-00690-9

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