Thymoquinone, a component derived from the medial plant Nigella sativa, has been used for medical purposes for more than 2,000 years. Recent studies reported that thymoquinone exhibited inhibitory effects on cell proliferation of many cancer cell lines and hormone-refractory prostate cancer by suppressing androgen receptor and E2F-1. Whether thymoquinone inhibits tumor angiogenesis, the critical step of tumor growth and metastasis, is still unknown. In this study, we found that thymoquinone effectively inhibited human umbilical vein endothelial cell migration, invasion, and tube formation. Thymoquinone inhibited cell proliferation and suppressed the activation of AKT and extracellular signal-regulated kinase. Thymoquinone blocked angiogenesis in vitro and in vivo, prevented tumor angiogenesis in a xenograft human prostate cancer (PC3) model in mouse, and inhibited human prostate tumor growth at low dosage with almost no chemotoxic side effects. Furthermore, we observed that endothelial cells were more sensitive to thymoquinone-induced cell apoptosis, cell proliferation, and migration inhibition compared with PC3 cancer cells. Thymoquinone inhibited vascular endothelial growth factor -induced extracellular signal-regulated kinase activation but showed no inhibitory effects on vascular endothelial growth factor receptor 2 activation. Overall, our results indicate that thymoquinone inhibits tumor angiogenesis and tumor growth and could be used as a potential drug candidate for cancer therapy.
Gambogic acid (GA), the main active compound of Gamboge hanburyi, has been previously reported to activate apoptosis in many types of cancer cell lines by targeting transferrin receptor and modulating nuclear factor-KB signaling pathway.
G-protein-coupled receptor (GPCR) 48 (Gpr48; Lgr4), a newly discovered member of the glycoprotein hormone receptor subfamily of GPCRs, is an orphan GPCR of unknown function. Using a knockout mouse model, we have characterized the essential roles of Gpr48 in bone formation and remodeling. Deletion of Gpr48 in mice results in a dramatic delay in osteoblast differentiation and mineralization, but not in chondrocyte proliferation and maturation, during embryonic bone formation. Postnatal bone remodeling is also significantly affected in Gpr48 -/-mice, including the kinetic indices of bone formation rate, bone mineral density and osteoid formation, whereas the activity and number of osteoclasts are increased as assessed by tartrate-resistant acid phosphatase staining. Examination of the molecular mechanism of Gpr48 action in bone formation revealed that Gpr48 can activate the cAMP-PKA-CREB signaling pathway to regulate the expression level of Atf4 in osteoblasts. Furthermore, we show that Gpr48 significantly downregulates the expression levels of Atf4 target genes/proteins, such as osteocalcin (Ocn; Bglap2), bone sialoprotein (Bsp; Ibsp) and collagen. Together, our data demonstrate that Gpr48 regulates bone formation and remodeling through the cAMP-PKA-Atf4 signaling pathway.
Morelloflavone, a biflavonoid extracted from Garcinia dulcis, has shown antioxidative, antiviral, and anti-inflammatory properties. However, the function and the mechanism of this compound in cancer treatment and tumor angiogenesis have not been elucidated to date. In this study, we postulated that morelloflavone might have the ability to inhibit angiogenesis, the pivotal step in tumor growth, invasiveness, and metastasis. We showed that morelloflavone could inhibit vascular endothelial growth factor (VEGF)-induced cell proliferation, migration, invasion, and capillary-like tube formation of primary cultured human umbilical vascular endothelial cells in a dose-dependent manner. Morelloflavone effectively inhibited microvessel sprouting of endothelial cells in the mouse aortic ring assay and the formation of new blood microvessels induced by VEGF in the mouse Matrigel plug assay. Furthermore, morelloflavone inhibited tumor growth and tumor angiogenesis of prostate cancer cells (PC-3) in xenograft mouse tumor model in vivo, suggesting that morelloflavone inhibited tumorigenesis by targeting angiogenesis. To understand the underlying mechanism of morelloflavone on the inhibitory effect of tumor growth and angiogenesis, we showed that morelloflavone could inhibit the activation of both RhoA and Rac1 GTPases but have little effect on the activation of Cdc42 GTPase. Additionally, morelloflavone inhibited the phosphorylation and activation of Raf/mitogen-activated protein kinase/extracellular signalregulated kinase (ERK) kinase/ERK pathway kinases without affecting VEGF receptor 2 activity. Together, our results indicate that morelloflavone exerts antiangiogenic action by targeting the activation of Rho-GTPases and ERK signaling pathways. These findings are the first to reveal the novel functions of morelloflavone in tumor angiogenesis and its molecular basis for the anticancer action. [Cancer Res 2009;69(2):518-25]
Kisspeptin-10 (Kp-10), a decapeptide derived from the primary translation product of KISS1 gene, has been previously reported to be a key hormone for puberty and an inhibitor for tumor metastasis via the activation of G protein-coupled receptor 54 (Gpr54). However, whether Kp-10 inhibits angiogenesis, which is critical for tumor growth and metastasis and other human diseases, is still unknown. Here we demonstrate that Kp-10 significantly inhibits human umbilical vein endothelial cell (HUEVC) migration, invasion, and tube formation, key processes in angiogenesis. Using chicken chorioallantoic membrane (CAM) assay and VEGF-induced mouse corneal micropocket assay, we demonstrate that Kp-10 inhibits angiogenesis in vivo. Furthermore, Kp-10 inhibits tumor growth in SCID mice xenografted with human prostate cancer cells (PC-3) through inhibiting tumor angiogenesis while Kp-10 has little effect on the proliferation of HUVECs and human prostate cancer cells. In deciphering the underlying molecular mechanisms, we demonstrate that Kp-10 suppresses VEGF expression by inhibiting the binding of Sp1 to VEGF promoter and by blocking the activation of c-Src/FAK and Rac/Cdc42 signaling pathway in HUVECs, leading to the inhibition of tumor angiogenesis.
Cancer inflammation promotes cancer progression, resulting in a high risk of cancer. Here, we demonstrate that our new herbal extract, SH003, suppresses both tumor growth and metastasis of MDA-MB-231 breast cancer cells via inhibiting STAT3-IL-6 signaling path. Our new herbal formula, SH003, mixed extract from Astragalus membranaceus, Angelica gigas, and Trichosanthes kirilowii Maximowicz, suppressed MDA-MB-231 tumor growth and lung metastasis in vivo and reduced the viability and metastatic abilities of MDA-MB-231 cells in vitro. Furthermore, SH003 inhibited STAT3 activation, which resulted in a reduction of IL-6 production. Therefore, we conclude that SH003 suppresses highly metastatic breast cancer growth and metastasis by inhibiting STAT3-IL-6 signaling path.
Tumor necrosis factor-alpha (TNFα) induces cancer development and metastasis, which is prominently achieved by nuclear factor-kappa B (NF-κB) activation. TNFα-induced NF-κB activation enhances cellular mechanisms including proliferation, migration, and invasion. KiSS1, a key regulator of puberty, was initially discovered as a tumor metastasis suppressor. The expression of KiSS1 was lost or down-regulated in different metastatic tumors. However, it is unclear whether KiSS1 regulates TNFα-induced NF-κB activation and further tumor cell migration. In this study, we demonstrate that KiSS1 suppresses the migration of breast cancer cells by inhibiting TNFα-induced NF-κB pathway and RhoA activation. Both KiSS1 overexpression and KP10 (kisspeptin-10) stimulation inhibited TNFα-induced NF-κB activity, suppressed TNFα-induced cell migration and cell attachment to fibronectin in breast cancer cells while KP10 has little effect on cancer cell proliferation. Furthermore, KP10 inhibited TNFα-induced cell migration and RhoA GTPase activation. Therefore, our data demonstrate that KiSS1 inhibits TNFα-induced NF-κB activation via downregulation of RhoA activation and suppression of breast cancer cell migration and invasion.
Kisspeptins are natural ligands of G protein-coupled receptor-54. Activation of KiSS1/G protein-coupled receptor-54 signaling pathways results in potent activation of the hypothalamus-pituitary-gonadal axis and initiates puberty. Recent data have shown that in female mice, KiSS1 is positively regulated by estradiol (E(2)) in the anteroventral periventricular nucleus, an important reproductive neuroendocrine brain region, but negatively regulated in the arcuate nucleus. However, little is known about the molecular mechanisms governing E(2)-modulated KiSS1 expression. Here, we demonstrate that the expression level of the KiSS1 gene was up-regulated with the administration of E(2) in estrogen receptor alpha (ERalpha)-positive hypothalamic GT1-7 cells. Using transient transfection of human KiSS1 gene promoter coupled to a luciferase reporter, E(2) increases promoter activity in the presence of ERalpha. Deletion analysis of KiSS1 promoter indicates that the E(2)-regulated increase in promoter activity depends on the Sp1 sites of the proximal promoter region. Using both EMSAs and chromatin immunoprecipitation analysis, we determined that both Sp1 and Sp3 proteins constitutively associate with the four putative Sp1 sites in vitro, whereas the association of ERalpha with the KiSS1 promoter is dependent on E(2) exposure. Sp1 and ERalpha form a complex in vivo to mediate the E(2)-induced activation of KiSS1 promoter. Interestingly, Sp1 transactivates KiSS1 promoter activity, whereas Sp3 functions as a transcriptional repressor. Together, these results demonstrate that E(2)-dependent transcriptional activation of KiSS1 gene is mediated by ERalpha through the interaction of Sp1/Sp3 proteins with the GC-rich motifs of KiSS1 promoter, providing a molecular mechanism of how steroid hormone feedback regulates KiSS1 expression.
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