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Istradefylline induces A2A/P2X7 crosstalk expression inducing pro-inflammatory signal, and reduces AKT/mTOR signaling in melanoma-bearing mice

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Abstract

ATP and adenosine (ADO) are critical players in the context of cancer. In the tumor microenvironment, the signaling dependent on these molecules, and immune cells, is regulated by an enzymatic chain and purinergic receptors called purinome. Primarily, the A2A receptor (A2AR) has a pro-tumor action since it reduces the immune response and favors the growth of malignant melanoma. Therefore, this study aimed to verify the effects of A2AR antagonism with Istradefylline (IST) on the purinergic signaling profile of the melanoma tumor and immunological compartments. We observed reduced tumor growth of melanoma in IST-treated animals. IST inhibited AKT/mTOR pathway, which is involved with tumor growth. In the tumor, spleen, and thymus, the modulation of purinergic enzymes (CD39, CD73, and E-ADA) characterized a pro-inflammatory profile since it favored increased extracellular concentrations of ATP to the detriment of ADO. A2AR inhibition generated a compensatory feedback process with increased A2AR expression at the tumor level. However, there was also an increase in the expression of the P2X7 receptor (P2X7R), which culminated in an increase in pro-inflammatory pathways with the release of IL-1β and pro-inflammatory cytokines such as IFN-γ and TNF-α. Our data evidence the cross-involvement between expression and action of the A2AR and P2X7R. We suggest that IST is a promising drug for off-label use in cancer since it promotes an anti-tumoral response by producing pro-inflammatory cytokines and blocking of AKT/mTOR tumor growth pathway.

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Funding

This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—Brasil (CAPES) -Finance Code 001, Grant Number 88887.338883/2019-00.

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Authors and Affiliations

  1. Laboratório de Imunobiologia Experimental e Aplicada (LABIBIO), Departamento de Microbiologia e Parasitologia, Centro de Ciências da Saúde, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil

    Jean L. Gutknecht da Silva, Daniela F. Passos, Fernanda L. Cabral, Andrieli A. Cardoso, Camile H. Dal Piva, Carolina O. Gomes, Renan S. Ebone & Daniela B. R. Leal

  2. Programa de Pós-Graduação em Bioquímica Toxicológica, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil

    Jean L. Gutknecht da Silva, Vanessa V. Miron, Maria R. C. Schetinger & Daniela B. R. Leal

  3. Departamento de Microbiologia e Parasitologia, Centro de Ciências da Saúde, Universidade Federal de Santa Maria, Av. Roraima, 1000, Prédio 20, Santa Maria, RS, 97105-900, Brazil

    Daniela B. R. Leal

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  1. Jean L. Gutknecht da Silva
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Contributions

Conceptualization: JLGdS, DBRL. Data curation: JLGdS, formal analysis JLGdS, DFP; investigation: JLGdS, VVM, RSE1. methodology: JLGdS, VVM, FLC, AAC1, CHDP1, COG1, project administration: JLGdS, DBRL; resources: DBRL, MRCS, supervision: DBRL, validation: DBRL, MRCS, visualization: JLGdS, DFP; roles/writing—original draf: JLGdS; writing—review & editing: JLGdS, DFP. All authors reviewed the manuscript.

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Correspondence to Daniela B. R. Leal.

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This project was approved by the Animals Use Ethics Commission of Universidade Federal de Santa Maria (CEUA/UFSM). The approval was granted under protocol number 4748290420.

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Gutknecht da Silva, J.L., Passos, D.F., Cabral, F.L. et al. Istradefylline induces A2A/P2X7 crosstalk expression inducing pro-inflammatory signal, and reduces AKT/mTOR signaling in melanoma-bearing mice. Med Oncol 40, 178 (2023). https://doi.org/10.1007/s12032-023-02033-6

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