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Alpha-1 antitrypsin expression is upregulated in multidrug-resistant cancer cells

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Abstract

Identification of the signature molecular profiles involved in therapy resistance is of vital importance in developing new strategies for treatments and disease monitoring. Protein alpha-1 antitrypsin (AAT, encoded by SERPINA1 gene) is an acute-phase protein, and its high expression has been linked with unfavorable clinical outcome in different types of cancer; however, data on its involvement in therapy resistance are still insufficient. We analyzed SERPINA1 mRNA expression in three different multidrug-resistant (MDR) cell lines—U87-TxR, NCI-H460/R, and DLD1-TxR—and in U87 cells grown in alginate microfibers as a 3D cellular model of glioblastoma. Expression of IL-6 as a major modulator of SERPINA1 was also analyzed. Additionally, AAT protein expression in MDR cells was analyzed by immunofluorescence. SERPINA1 gene expression and AAT protein expression were significantly upregulated in all the tested MDR cell lines compared with their sensitive counterparts. Moreover, SERPINA1 was significantly upregulated in 3D models of glioblastoma, previously found to have upregulated drug-resistance-related gene expression compared with 2D cells. With the exception of NCI-H460/R, in all cell lines as well as in a 3D model of U87 cells, increase in SERPINA1 expression correlated with the increase in IL-6 expression. Our results indicate that AAT could be utilized as a biomarker of therapy resistance in cancer; however, further studies are needed to elucidate the mechanisms driving AAT upregulation in therapy resistance and its biological significance in this process.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Funding

This work was supported by Ministry of Education, Science and Technological Development of the Republic of Serbia (ref. number 451–03-68/2022–14/200042 and 451–03-68/2022–14/ 200007).

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Authors and Affiliations

  1. Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia

    Aleksandra Divac Rankov & Mila Ljujić

  2. Department of Neurobiology, Institute for Biological Research “Sinisa Stankovic” - National Institute of Republic of Serbia, University of Belgrade, Belgrade, Serbia

    Sofija Jovanović Stojanov & Miodrag Dragoj

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  1. Aleksandra Divac Rankov
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  2. Sofija Jovanović Stojanov
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  3. Miodrag Dragoj
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  4. Mila Ljujić
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Contributions

ML: conceptualization. ML, MD, SJS, ADR: design of experiments. ML, SJS, MD: performance of experiments. ML, ADR: analysis of experiments. ML: preparation of original draft. ML, ADR, SJS, MD: review and editing. All authors read and approved the final manuscript.

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Correspondence to Mila Ljujić.

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Divac Rankov, A., Jovanović Stojanov, S., Dragoj, M. et al. Alpha-1 antitrypsin expression is upregulated in multidrug-resistant cancer cells. Histochem Cell Biol 159, 431–437 (2023). https://doi.org/10.1007/s00418-022-02172-3

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