## 4 Role of Ap4A: Functions in Normal and Cancer Cells
### Interaction with Purinergic Receptors
#### 4.5.6 P2Y Receptors  
P2 receptors are widely expressed across various cancer types, with their activation or inhibition influencing tumor cell survival and proliferation. These findings have sparked growing interest in targeting P2 receptor signaling as a potential therapeutic strategy for cancer treatment [48]. P2Y receptors are a family of G protein-coupled receptors (GPCRs) that respond to extracellular nucleotides such as ATP, ADP, UTP, and UDP. Unlike ionotropic P2X receptors, P2Y receptors mediate their effects through second messenger systems, triggering a variety of intracellular responses [49]. There are eight known subtypes of P2Y receptors: P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y12, P2Y13, and P2Y14, which are involved in physiological processes such as platelet aggregation, immune response, and regulation of vascular tone. Extensive research highlights the strong association between platelets and cancer progression. Ap4A's interaction with P2Y receptors significantly impacts cancer cell behaviour by modulating signaling pathways that control proliferation, migration, and apoptosis. For example, Ap4A acts as an agonist at P2Y1 receptors, which are involved in regulating cancer cell proliferation and migration [50]. This interaction is critical in modulating intracellular pathways that promote tumor progression. Similarly, P2Y2 receptors, which respond to ATP and UTP, regulate cell survival and apoptosis. When Ap4A binds to P2Y2, it influences these processes, potentially affecting tumor growth and resistance to cell death [51]. Moreover, the dual role of Ap4A is particularly evident in ocular physiology. [PERSON] et al. [52] identified Ap4A and Ap5A as soluble components of the human aqueous humour and reported significantly elevated Ap4A levels in patients with glaucoma compared to healthy individuals. In this context, Ap4A was found to increase intraocular pressure (IOP) by stimulating P2Y2 receptors on the ciliary body, a mechanism associated with disease progression. Paradoxically, other studies have demonstrated that Ap4A can also lower IOP by activating P2Y6 receptors in the ciliary processes, suggesting a protective role in glaucoma models [53]. These contrasting effects underscore the complexity of Ap4A's biological functions and highlight the importance of receptor-specific signaling in determining its physiological or pathological outcomes. P2Y12R, plays a key role in platelet activation, facilitating aggregation and adhesion to cancer cells. This process supports extravasation and metastasis by enabling cancer cells to navigate the vascular system more effectively. Currently, P2Y12R inhibitors are primarily used as antiplatelet agents. However, their impact on tumor progression is complex and dual-faceted. While some studies suggest that inhibiting P2Y12R suppresses tumor growth and metastasis, others indicate that P2Y12R inhibitors may, in certain contexts, facilitate tumor development. Given these contrasting effects, careful evaluation is necessary when considering P2Y12R inhibitors for anticancer applications, balancing their potential benefits with associated risks. In the context, the interaction between P2Y12 receptors and Ap4 Amay influence metastasis by affecting platelet-tumor cell interactions, which are crucial for the dissemination of cancer cells to distant sites [54]. Moreover, diadenosine tetraphosphate holds therapeutic promise for patients at high risk of coronary thrombosis due to their rapid, reversible action and intravenous administration [55]. Ap4A can also modulate the tumor immune microenvironment by activating P2Y receptors, influencing immune cell infiltration and activity. By altering these immune interactions, Ap4A may affect the anti-tumor immune response and contribute to immune evasion by the tumor [56]. In addition to its role in cancer, Ap4A has been shown to interact with P2Y1 receptors in smooth muscle regulation.