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Targeted Inhibition of Hsp90 in Combination with Metformin Modulates Programmed Cell Death Pathways in A549 Lung Cancer Cells

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Abstract

The pathophysiology of lung cancer is dependent on the dysregulation in the apoptotic and autophagic pathways. The intricate link between apoptosis and autophagy through shared signaling pathways complicates our understanding of how lung cancer pathophysiology is regulated. As drug resistance is the primary reason behind treatment failure, it is crucial to understand how cancer cells may respond to different therapies and integrate crosstalk between apoptosis and autophagy in response to them, leading to cell death or survival. Thus, in this study, we have tried to evaluate the crosstalk between autophagy and apoptosis in A549 lung cancer cell line that could be modulated by employing a combination therapy of metformin (6 mM), an anti-diabetic drug, with gedunin (12 µM), an Hsp90 inhibitor, to provide insights into the development of new cancer therapeutics. Our results demonstrated that metformin and gedunin were cytotoxic to A549 lung cancer cells. Combination of metformin and gedunin generated ROS and promoted MMP loss and DNA damage. The combination further increased the expression of AMPKα1 and promoted the nuclear localization of AMPKα1/α2. The expression of Hsp90 was downregulated, further decreasing the expression of its clients, EGFR, PIK3CA, AKT1, and AKT3. Inhibition of the EGFR/PI3K/AKT pathway upregulated TP53 and inhibited autophagy. The combination was promoting nuclear localization of p53; however, some cytoplasmic signals were also detected. Further increase in the expression of caspase 9 and caspase 3 was observed. Thus, we concluded that the combination of metformin and gedunin upregulates apoptosis by inhibiting the EGFR/PI3K/AKT pathway and autophagy in A549 lung cancer cells.

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Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

The authors are thankful to Hon’ble Vice-Chancellor, Integral University, Lucknow, for providing infrastructural support and Dean Office, R&D, Integral University, for providing manuscript communication number (IU/R&D/2021-MCN0001317). The author, A.H., is thankful to SERB-DST for providing the fellowship.

Funding

This work was supported by the Science & Engineering Research Board (SERB-DST) (grant number: YSS/2015/001902, awarded to SSM).

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Authors and Affiliations

  1. Molecular Cell Biology Laboratory, Integral Information and Research Centre-4 (IIRC-4), Integral University, Kursi Road, Lucknow, 226026, India

    Adria Hasan & Snober S. Mir

  2. Department of Bioengineering, Faculty of Engineering, Integral University, Kursi Road, Lucknow, 226026, India

    Adria Hasan

  3. Current Address: Cancer Prevention and Control Program, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA

    Adria Hasan

  4. Department of Medical Laboratories Technology, College of Applied Medical Sciences, Jazan University, Jazan, 45142, Kingdom of Saudi Arabia

    Nizar Khamjan

  5. Medical Research Center, Faculty of Applied Medical Sciences, Jazan University, Jazan, Kingdom of Saudi Arabia

    Mohtashim Lohani

  6. Emergency Medical Services, Faculty of Applied Medical Sciences, Jazan University, Jazan, Kingdom of Saudi Arabia

    Mohtashim Lohani

  7. Department of Biosciences, Faculty of Science, Integral University, Kursi Road, Lucknow, 226026, India

    Snober S. Mir

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  1. Adria Hasan
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Conceptualization: AH, SSM; experiment performance: AH; material preparation, data collection, and analysis: AH and SSM; writing—original draft preparation: AH and SSM; writing—review and editing: AH, SSM, NK, ML; funding acquisition: SSM; resources: SSM; supervision: SSM.

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Correspondence to Snober S. Mir.

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Hasan, A., Khamjan, N., Lohani, M. et al. Targeted Inhibition of Hsp90 in Combination with Metformin Modulates Programmed Cell Death Pathways in A549 Lung Cancer Cells. Appl Biochem Biotechnol 195, 7338–7378 (2023). https://doi.org/10.1007/s12010-023-04424-x

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