curcumin and lysophosphatidic-acid

Curcumin is a natural compound that has been widely used as a food additive and medicine in Asian countries. Over several decades, diverse biological effects of curcumin have been elucidated, such as anti-inflammatory and anti-oxidative activities. Monocyte chemoattractant protein-1 (MCP-1) is a key inflammatory marker during the development of atherosclerosis, and curcumin blocks MCP-1 expression stimulated by various ligands. Hence, we studied the action of curcumin on lysophosphatidic acid (LPA) mediated MCP-1 expression and explored the specific underlying mechanisms. In human vascular smooth muscle cells, LPA induces Rho-associated protein kinase (ROCK) dependent transforming growth factor receptor (TGFBR1) transactivation, leading to glycosaminoglycan chain elongation. We found that LPA also signals via the TGFBR1 transactivation pathway to regulate MCP-1 expression. Curcumin blocks LPA mediated TGFBR1 transactivation and subsequent MCP-1 expression by blocking the ROCK signalling. In the vasculature, ROCK signalling regulates smooth muscle cell contraction, inflammatory cell recruitment, endothelial dysfunction and vascular remodelling. Therefore, curcumin as a ROCK signalling inhibitor has the potential to prevent atherogenesis via multiple ways.

Topics: Animals; Blotting, Western; Cell Line; Cell Survival; Chemokine CCL2; Curcumin; Humans; Inflammation; Lysophospholipids; Muscle, Smooth, Vascular; Receptors, Transforming Growth Factor beta; rho-Associated Kinases; Signal Transduction

Breast cancer generally shows poor prognosis because of its invasion and metastasis. Lysophosphatidic acid (LPA) induces and aggravates cancer invasion and metastasis by activating its downstream signal pathways. RhoA/ROCK/MMP signaling was found one of the LPA-induced pathways, which may be involved in invasion of breast cancer. Furthermore, we investigated whether this pathway was involved in curcumin's effect against LPA-induced invasion. LPA incubation was used to enhance invasion of MCF-7 breast cancer cells. RhoA expression was knocked-down by siRNA technique. MTT assay was used to evaluate the proliferation. Transwell assay was utilized to investigate the invasion ability of MCF-7 cells. Real-time PCR and Western blotting were used to assess the expressions of RhoA, ROCK1, ROCK2, MMP2 and MMP9 at both translational and transcriptional levels. The RhoA and ROCK activities were also evaluated. LPA incubation significantly boosted invasion rate of MCF-7. RhoA silencing by siRNA dramatically inhibited LPA-enhanced invasion. Concurrently, RhoA and ROCK activities and expression levels of RhoA, ROCK1, ROCK2, MMP2 and MMP9 were down-regulated by RhoA siRNA transfection. In order to avoid influence of cytotoxicity of curcumin, concentrations below 45 μmol/L were selected to further investigate the mechanism of curcumin's anti-invasion effect. Invasion of LPA-incubated MCF-7 cells was impaired by curcumin in a concentration-dependent manner. Concurrently, RhoA and ROCK activities and expression levels of RhoA, ROCK1, ROCK2, MMP2 and MMP9 were down-regulated by curcumin in a concentration-dependent manner. In conclusion, RhoA/ROCK/MMPs pathway activation is involved in LPA-induced invasion in MCF-7 cells; curcumin inhibited LPA-induced invasion in MCF-7 cells by attenuating RhoA/ROCK/MMPs pathway.

Topics: Antineoplastic Agents; Breast Neoplasms; Cell Movement; Cell Proliferation; Curcumin; Female; Gene Expression Regulation, Neoplastic; Humans; Lysophospholipids; Matrix Metalloproteinases; MCF-7 Cells; Neoplasm Invasiveness; rho-Associated Kinases; rhoA GTP-Binding Protein; Signal Transduction

Connective tissue growth factor (CTGF/CCN2) is involved in the development and progression of fibrotic diseases, including gingival overgrowth (GO). Recent studies indicate that lysophosphatidic acid (LPA) is also significantly involved in wound healing and the development of fibrosis. This study investigated whether epigallocatechin-3-gallate (EGCG) can inhibit LPA-induced CCN2 expression in human gingival fibroblast (GF) and its mechanism.. Western blot analyses were used to study the signaling pathways of LPA-induced CCN2 expression in human GFs and the effects of EGCG on this pathway.. LPA stimulated CCN2 synthesis in human GFs. This effect can be significantly inhibited bytransforming growth factor-β type I receptor/ALK5, Smad3, and JNK inhibitors but not ERK, P38, and MAPK inhibitors. EGCG completely inhibited LPA-induced CCN2 expression through attenuating the LPA-induced JNK and Smad3 phosphorylation in human GFs.. LPA produced at the surgical wound may contribute to the recurrence of GO by upregulating CCN2 expression in human GFs. This effect was mediated by Smad3 and JNK activation and ALK5 transactivation. EGCG could be a useful agent for reducing the recurrence of GO after surgery through suppression of JNK and Smad3 activations.

Topics: Catechin; Cells, Cultured; Connective Tissue Growth Factor; Curcumin; Fibroblasts; Gingiva; Humans; Lysophospholipids; MAP Kinase Kinase 4; Smad3 Protein; Wound Healing

Lysophosphatidic acid (LPA) is a biolipid that stimulates tumor cell invasion and metastasis. In this report, we determined the role of signal transducers and activators of transcription 3 (STAT3) and the effect of a chemopreventive agent, curcumin, on LPA-induced ovarian cancer cell motility. LPA phosphorylated STAT3 in a dose-dependent manner. Treatment of cells with a JAK/STAT inhibitor, AG490, inhibited LPA-induced cell motility. In contrast, transfection of a constitutively active form of STAT3 induced ovarian cancer cell motility. LPA also stimulated interleukin (IL)-6 and IL-8 secretion, which results in STAT3 phosphorylation. Treatment of the cells with curcumin inhibited LPA-induced IL-6 and IL-8 secretion and STAT3 phosphorylation, leading to blocked ovarian cancer cell motility. Collectively, the present study shows the critical role of STAT3 in ovarian cancer cell motility and that this process can be prevented by curcumin.

Topics: Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Cell Movement; Cell Survival; Curcumin; Dose-Response Relationship, Drug; Female; Humans; Interleukin-6; Interleukin-8; Janus Kinases; Lysophospholipids; Neoplasm Invasiveness; Ovarian Neoplasms; Phosphorylation; Protein Kinase Inhibitors; Signal Transduction; STAT3 Transcription Factor; Transfection; Tyrphostins