Abstract
5-Hydroxytryptamine (5-HT) induces proliferation of cancer cells and vascular cells. In addition to 5-HT production by several cancer cells including gastrointestinal and breast cancer, a significant level of 5-HT is released from activated platelets in the thrombotic environment of tumors, suggesting that inhibition of 5-HT signaling may constitute a new target for antiangiogenic anticancer drug discovery. In the current study we clearly demonstrate that 5-HT-induced angiogenesis was mediated through the 5-HT1 receptor-linked Gβγ/Src/PI3K pathway, but not through the MAPK/ERK/p38 pathway. In addition, 5-HT induced production of NADPH oxidase (NOX)-derived reactive oxygen species (ROS). In an effort to develop new molecularly targeted anticancer agents against 5-HT action in tumor growth, we demonstrate that BJ-1108, a derivative of 6-amino-2,4,5-trimethylpyridin-3-ol, significantly inhibited 5-HT-induced angiogenesis. In addition, BJ-1108 induced a significant reduction in the size and weight of excised tumors in breast cancer cell-inoculated CAM assay, showing proportionate suppression of tumor growth along with inhibition of angiogenesis. In human umbilical vein endothelial cells (HUVECs), BJ-1108 significantly suppressed 5-HT-induced ROS generation and phosphorylation of PI3K/Akt but not of Src. Unlike NOX inhibitors, BJ-1108, which showed better antioxidant activity than vitamin C, barely suppressed superoxide anion induced by mevalonate or geranylgeranyl pyrophosphate which directly activates NOX without help from other signaling molecules in HUVECs, implying that the anti-angiogenic action of BJ-1108 was not mediated through direct action on NOX activation, or free radical scavenging activity. In conclusion, BJ-1108 inhibited 5-HT-induced angiogenesis through PI3K/NOX signaling but not through Src, ERK, or p38.
Highlights
Angiogenesis is the process of generating new blood vessels from pre-existing ones
Our current results showing that AZM-475271 (Src inhibitor) and wortmannin (PI3K inhibitor) suppressed 5-HT-induced reactive oxygen species (ROS) indicate that NADPH oxidase (NOX) activation by 5-HT is mediated through the 5-HT1 receptor-linked Src/PI3K pathway, which is consistent with observations of other types of G-protein coupled receptors (GPCRs) including CXCR2 [chemokine (C-X-C motif) receptor 2] and AT1R
PI3K plays a critical role in angiogenesis [43, 44] as well as cancer cell proliferation, migration, invasion, survival, and malignant transformation [45], it is as an attractive molecular target for development of an antiangiogenic anticancer drug [46, 47]
Summary
Angiogenesis is the process of generating new blood vessels from pre-existing ones. Normal angiogenesis is a critical process for organ development as well as reproduction and wound healing. Uncontrolled abnormal angiogenesis is associated with the pathogenesis of various diseases including rheumatoid arthritis, age-related macular degeneration, and diabetic retinopathy [1,2,3], and is involved in tumor growth and metastasis. Suppression of such pathological angiogenesis has been a promising approach in prevention and treatment of the diseases. Cancer and stromal cells in tumor tissues produce a number of angiogenesis inducers including growth factors such as vascular endothelial growth factor (VEGF) and plateletderived growth factor (PDGF), and cytokines such as interleukin (IL)-8 [4,5,6]. Due to its invasive nature, cancer is associated with thromboembolic complications [15,16,17,18], and in such a thrombotic environment, cancer cells activate platelets to release significant levels of 5-HT, leading to direct action in endothelial cells to induce vasoconstriction, platelet thrombus formation [19, 20], and angiogenesis [13]
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