Exosomes, small-sized extracellular vesicles, carry components of the purinergic pathway. The production by cells of exosomes carrying this pathway remains poorly understood. Here, we asked whether type 1, 2A, or 2B adenosine receptors (A₁Rs, A_2ARs, and A_2BRs, respectively) expressed by producer cells are involved in regulating exosome production. Preglomerular vascular smooth muscle cells (PGVSMCs) were isolated from wildtype, A₁R^−/−, A_2AR^−/−, and A_2BR^−/− rats, and exosome production was quantified under normal or metabolic stress conditions. Exosome production was also measured in various cancer cells treated with pharmacologic agonists/antagonists of A₁Rs, A_2ARs, and A_2BRs in the presence or absence of metabolic stress or cisplatin. Functional activity of exosomes was determined in Jurkat cell apoptosis assays. In PGVSMCs, A₁R and A_2AR constrained exosome production under normal conditions (p = 0.0297; p = 0.0409, respectively), and A₁R, A_2AR, and A_2BR constrained exosome production under metabolic stress conditions. Exosome production from cancer cells was reduced (p = 0.0028) by the selective A_2AR agonist CGS 21680. These exosomes induced higher levels of Jurkat apoptosis than exosomes from untreated cells or cells treated with A₁R and A_2BR agonists (p = 0.0474). The selective A_2AR antagonist SCH 442416 stimulated exosome production under metabolic stress or cisplatin treatment, whereas the selective A_2BR antagonist MRS 1754 reduced exosome production. Our findings indicate that A_2ARs suppress exosome release in all cell types examined, whereas effects of A₁Rs and A_2BRs are dependent on cell type and conditions. Pharmacologic targeting of cancer with A_2AR antagonists may inadvertently increase exosome production from tumor cells.

中文翻译：

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腺苷受体调节外泌体的产生。

外泌体是小型细胞外囊泡，携带嘌呤能途径的成分。携带该途径的外泌体细胞的产生仍然知之甚少。在这里，我们询问生产细胞表达的 1、2A 或 2B 型腺苷受体（分别为 A ₁ Rs、A _2A Rs 和 A _2B Rs）是否参与调节外泌体的产生。从野生型、A ₁ R ^−/−、A _2A R ^−/−和 A _2B R ^−/−大鼠中分离出肾小球前血管平滑肌细胞 (PGVSMC)，并在正常或代谢应激条件下量化外泌体的产生。在存在或不存在代谢应激或顺铂的情况下，还测量了用 A ₁ Rs、A _2A Rs 和 A _2B Rs的药理学激动剂/拮抗剂处理的各种癌细胞中的外泌体产生。外泌体的功能活性在 Jurkat 细胞凋亡测定中测定。在 PGVSMC 中，A ₁ R 和 A _2A R 在正常条件下限制外泌体产生（分别为p  = 0.0297；p  = 0.0409），而 A ₁ R、A _2A R 和 A _2B R 在代谢应激条件下限制外泌体产生。 选择性 A _2A R 激动剂 CGS 21680减少了癌细胞产生的外泌体 ( p = 0.0028)。与未经处理的细胞或用 A ₁ R 和 A _2B R 激动剂处理的细胞的外泌体相比，这些外泌体诱导更高水平的 Jurkat 细胞凋亡 ( p  = 0.0474）。选择性 A _2A R 拮抗剂 SCH 442416 在代谢应激或顺铂治疗下刺激外泌体产生，而选择性 A _2B R 拮抗剂 MRS 1754 减少外泌体产生。我们的研究结果表明，A _2A Rs 抑制所有检查细胞类型中的外泌体释放，而 A ₁ Rs 和 A _2B Rs 的作用取决于细胞类型和条件。_{使用 A 2A} R 拮抗剂对癌症进行药理学靶向可能会无意中增加肿瘤细胞的外泌体产量。