Serotonin: a potential upstream regulator of platelet‐derived growth factor

We read the recent Journal of Cellular Biochemistry article published by Smoot et al with great interest. The author first proved that platelet-derived growth factor (PDGF) was associated with YAP transcriptional activity in cholangiocarcinoma (CCA). In the study, platelet-derived growth factor receptor (PDGFR), nucleus located YAP, and YAP transcriptional activity all increased in human and mouse CCA specimens, cell lines, and patient-derived xenografts. Further study demonstrated that subcellular compartmentation and transcriptional activity of YAP were regulated by PDGFR pathway. Finally, the PDGFR-SFK-YAP tyrosine phosphorylation cascade emerged out. Though, PDGFRwas found to be an upstream regulator of YAPbySmoot et al. If PDGFRpathwaycould be regulated and what was the regulator were still undetermined. Here, we want to point out that serotonin, acted as a mitogen in kinds of cancer, might be a potential upstream regulator of PDGF. The study conducted by Liu et al first demonstrated that 5-HT transporter had the ability to transactivate the PDFGR in smooth muscle cells. Simultaneously, serotonin was proved to promote proliferation of smooth muscle cells through 5-HT receptors and 5-HT transporter in their study. A follow-up study conducted by Ren et al also indicated that serotonin transporter could promote proliferation of pulmonary artery smooth muscle cells by interacting with the PDGFβ receptor. Moreover, blocking 5-HT transporter activated by serotonin could inhibited PDGF induced proliferation, whereas, 5-HT1B or 5-HT2A receptor inhibitors did not seem to offer this effect. Besides in smooth muscle cells, PDGFβ receptor was upregulated by activated 5-HT7 receptor in neurons. In the study, the expression of PDGFβ receptor inmouse neurons and human neuroblastoma cell line SH-SY5Y cells incubated with 5-HT or 5-HT7 receptor agonists were increased. 4 Similar study also demonstrated that 5-HT7 receptor activation in primary hippocampal neurons could upregulate the expression of PDGFβ receptor and phospholipase C (PLC) γ, which was a downstream effector of PDGFβ receptor. Moreover, Kruk et al found that serotonin could promote phosphorylation of PDGFβ receptor via 5-HT1A receptor. And ERK1/2 phosphorylation caused by PDGFβ receptor also increased by serotonin administration.A study conducted byKruk et al also showed similar results. Excepted for 5-HT1B or 5-HT2A receptor, 5-HT receptors activated by serotonin could regulated the expression of PDGFβ receptor. Thus, serotonin was an upstream regulator of PDGF receptor in neurons and smooth muscle cells, and activated 5-HT transporter or 5-HT receptors could regulate PDGF receptor. In addition, our previous study demonstrated that serotonin activated 5-HT1A, 5-HT1B, 5-HT2B, and 5-HT7 receptors, especially the 5-HT2B receptor in liver cancer. The expression of YAP was also upregulated by serotonin via ERK1/2 phosphorylation. Besides, serotonin was proved to promote growth of several kinds of tumors via 5-HT1B, 5HT1D, and 5-HT2B receptors. 8,9 Thus, 5-HT receptors activated by serotonin was associated with cancer progression. Based on the results obtained by Smoot et al that PDGF receptors regulated YAP transcriptional activity in CCA. We supposed that serotonin might regulate PDGFR via activating 5-HT receptors in cancer. In conclusion, serotonin might be a potential upstream regulator of PDGFR and regulated its expression via activating 5-HT receptors in cancers.Moreover, basedon all these results, serotonin might promote tumor progression in a 5HT-5HT receptor-PDGFR-YAP axis in cancers. However, more experimental and clinical researches needed to confirm the relationship of serotonin and PDGFR in cancers.