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NRF2 Suppression Enhances the Susceptibility of Pancreatic Cancer Cells, Miapaca-2 to Paclitaxel

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Abstract

Pancreatic cancer is one of the most deadly diseases, with a very high metastasis and low survival rate. High levels of NRF2 have been detected in numerous malignancies, including head, neck, lung, and colon cancers, promoting the expansion and survival of cancer cells and chemical resistance to stressful conditions and affecting the response to treatment. To evaluate the possibility that modulation of NRF2 expression could be effective in treating pancreatic cancer cells, we explored the effect of knockdown of the NRF2 gene by NRF2-specific siRNA and its influence in combination with paclitaxel on pancreatic cancer cells. Miapaca-2 cell line, due to the high expression of the NRF2 gene, was selected for this study. Then, Miapaca-2 cells in different groups were treated with NRF2 siRNA and paclitaxel separately and in combination. After that, cell viability was measured by MTT assay and apoptosis induction by Annexin V-FITC/PI staining test. Cell cycle and autophagy were examined by flow cytometry, and cell migration was assessed by wound-healing assay. Finally, the expression of genes involved in apoptosis, Bax, Caspase-3, Caspase-9, and genes related to migration pathway, MMP-2, and MMP-9 in different groups were measured using qRT-PCR. Combined use of NRF2-specific siRNA with paclitaxel significantly reduced NRF2 gene expression in pancreatic cancer cells. NRF2 siRNA transfection significantly reduced cell viability. In addition, paclitaxel combination therapy with NRF2 siRNA strengthens the anti-tumor effects, such as inhibiting cell migration and provoking apoptosis, and autophagy and the cell cycle arrest in the G2 phase. NRF2 suppression augmented the expression of Bax, Caspase-3, and Caspase-9 genes and lowered the expression of Bcl-2, MMP-2, and MMP-9 genes, which play crucial roles in the pathways of apoptosis and cell migration, respectively. NRF2 siRNA enhances the susceptibility of Miapaca-2 cells to paclitaxel in pancreatic cancer cells. Thereby, suppressing NRF2 in combination with paclitaxel can be a new and efficacious treatment approach in treating pancreatic cancer.

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Data Availability

The data that support the findings of this study are available on request from the corresponding Author.

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Acknowledgements

All the authors would like to thank the Immunology Research Center of Tabriz University of Medical Sciences for their kind support during this study.

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Authors and Affiliations

  1. Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran

    Negin Riazi-Tabrizi, Mohammad Khalaj-Kondori, Mohadeseh Maghsoudi & Shima Hasani

  2. Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

    Sahar Safaei, Mohammad Amini, Hamidreza Hassanian & Behzad Baradaran

  3. Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran

    Behzad Baradaran

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  1. Negin Riazi-Tabrizi
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  2. Mohammad Khalaj-Kondori
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Correspondence to Mohammad Khalaj-Kondori or Behzad Baradaran.

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The research protocol was approved by the Ethics Committee of Tabriz University of Medical Sciences, Iran (IR.TBZMED.VCR.REC.1400.329).

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Riazi-Tabrizi, N., Khalaj-Kondori, M., Safaei, S. et al. NRF2 Suppression Enhances the Susceptibility of Pancreatic Cancer Cells, Miapaca-2 to Paclitaxel. Mol Biotechnol (2023). https://doi.org/10.1007/s12033-023-00872-2

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