## 4 Role of Ap4A: Functions in Normal and Cancer Cells
### Interaction with Purinergic Receptors
#### 4.5.6 P2Y Receptors
It has been demonstrated that Ap4A activates P2Y1 receptors in the circular smooth muscle of the mouse colon, causing muscle hyperpolarization and inhibition of spontaneous contractions [57]. In summary, Ap4A interacts with both P2X and P2Y receptors, influencing various aspects of cell biology (Table 1). These interactions affect processes such as angiogenesis, tumor growth, immune responses, and metastatic potential, underscoring the complex role of Ap4A in the TME. Targeting Ap4A and its associated signaling pathways offers promising avenues for developing anticancer therapies aimed at disrupting tumor-supporting interactions and enhancing the efficacy of existing treatments. \begin{table}
\begin{tabular}{c c c c c} \hline \hline
**Receptor** & **Type** & **Ap4A Role** & **Cancer Implications** & **Therapeutic Avenues** & **Ref.** \\ \hline \multirow{4}{*}{P2X1} & \multirow{4}{*}{Ionotropic} & Acts as an agonist; promotes endothelial cell proliferation and migration & Facilitates angiogenesis, supporting tumor growth by supplying oxygen and nutrients. & Proliferation of highly malignant T24 bladder cancer cells depended on autocrine signaling through P2X receptors & [41; 58] \\  & & & & \\ \hline \multirow{4}{*}{P2X3} & \multirow{4}{*}{Ionotropic} & Possible interaction with cancer pain pathways & May influence tumor-induced pain and tissue remodelling. & P2X3 purnergeis receptor & \\  & & & & & \\ \cline{1-1}  & & & & & \\ \cline{1-1}  & & & & & \\ \cline{1-1}  & & & & & \\ \cline{1-1}  & & & & & \\ \hline \multirow{4}{*}{P2X4} & \multirow{4}{*}{Ionotropic} & Activates endothelial cells; enhances pro-angiogenic cytokine release & Promotes vascularization within tumors, aiding their survival in hypoxic environments. & P2X4R activation enhances the invasiveness of prostate cancer & [58; 61] \\ \cline{1-1}  & & & & & \\ \hline \multirow{4}{*}{P2X5} & \multirow{4}{*}{Ionotropic} & Supports & Potentially contributes to uncontrolled tumor & P2X5 is highly expressed in a broad range of cell growth & [47; 62] \\  & & tissue proliferation & cell growth & lymphoid malignancies & \\ \hline \multirow{4}{*}{P2X7} & \multirow{4}{*}{Ionotropic} & Indirect modulation; triggers pro-inflammatory cytokine release & Contributes to the tumor’s inflammatory microenvironment and immune evasion. & P2X7R was highly expressed in gastric cancer tissues and gastric cancer cells & [45; 63] \\ \cline{1-1}  & & & & & \\ \cline{1-1}  & & & & \\ \cline{1-1}  & & & & & \\ \hline \multirow{4}{*}{P2Y1} & \multirow{4}{*}{Metabotropic} & Agonist; regulates cell proliferation and migration & Modulates intracellular signaling pathways critical for tumor progression. & Novel P2Y1 receptor ligands as a potent anti-prostate cancer agent & [64; 65] \\ \cline{1-1}  & & & & & \\ \hline \multirow{4}{*}{P2Y2} & \multirow{4}{*}{Metabotropic} & Regulates cell survival and apoptosis & Promotes tumor resistance to cell death and enhances survival under stress conditions. & P2Y2 antagonism promoted apoptosis in HCC cells Human and murine oral cancer cell lines express numerous P2 receptors & [66; 67] \\ \cline{1-1}  & & & & & \\ \cline{1-1}  & & & & & \\ \cline{1-1}  & & & & & \\ \hline \multirow{4}{*}{P2Y6} & \multirow{4}{*}{Metabotropic} & Activates during stress; influences metabolism and immune response & Modulates tumor adaptation and immune system interactions. & P2Y\({}_{\text{e}}\)R may represent a porcine target for reducing colorectal carcinogenesis & [68; 69] \\ \cline{1-1}  & & & & & \\ \hline \multirow{4}{*}{P2Y12} & \multirow{4}{*}{Metabotropic} & Affects platelet aggregation and tumor cell interactions & Facilitates metastasis by enabling dissemination via the circulatory system. & P2Y12 inhibitors could reduce the tumor spread in melanoma, ovarian, breast, lung and pancreatic cancers & [70; 71] \\ \cline{1-1}  & & & & & \\ \cline{1-1}  & & & & & \\ \hline \end{tabular}
\end{table} 
Table 1: Summary of Ap4A interactions with purinergic receptors and their implications.