BackgroundDiosgenin, a steroidal saponin obtained from fenugreek (Trigonella foenum graecum), was found to exert anti-carcinogenic properties, such as inhibiting proliferation and inducing apoptosis in a variety of tumor cells. However, the effect of diosgenin on cancer metastasis remains unclear. The aim of the study is to examine the effect of diosgenin on migration and invasion in human prostate cancer PC-3 cells.Methods and Principal FindingsDiosgenin inhibited proliferation of PC-3 cells in a dose-dependent manner. When treated with non-toxic doses of diosgenin, cell migration and invasion were markedly suppressed by in vitro wound healing assay and Boyden chamber invasion assay, respectively. Furthermore, diosgenin reduced the activities of matrix metalloproteinase-2 (MMP-2) and MMP-9 by gelatin zymography assay. The mRNA level of MMP-2, -9, -7 and extracellular inducer of matrix metalloproteinase (EMMPRIN) were also suppressed while tissue inhibitor of metalloproteinase-2 (TIMP-2) was increased by diosgenin. In addition, diosgenin abolished the expression of vascular endothelial growth factor (VEGF) in PC-3 cells and tube formation of endothelial cells. Our immunoblotting assays indicated that diosgenin potently suppressed the phosphorylation of phosphatidylinositide-3 kinase (PI3K), Akt, extracellular signal regulating kinase (ERK) and c-Jun N-terminal kinase (JNK). In addition, diosgenin significantly decreased the nuclear level of nuclear factor kappa B (NF-κB), suggesting that diosgenin inhibited NF-κB activity.Conclusion/SignificanceThe results suggested that diosgenin inhibited migration and invasion of PC-3 cells by reducing MMPs expression. It also inhibited ERK, JNK and PI3K/Akt signaling pathways as well as NF-κB activity. These findings reveal new therapeutic potential for diosgenin in anti-metastatic therapy.
Glycoalkaloids are the biologically active secondary metabolites found in many plants, such as potatoes. Glycoalkaloids are produced in leaves, roots, tubers and sprouts of the potato plant, and are involved in host plant resistance to bacteria, fungi, viruses, and insects.1) Several reports have showed that glycoalkaloids suppress the growth of cancer cells in human skin, liver, prostate, breast and colon.2-4) aSolanine, a trisaccharide glycoalkaloid, is one of the main steroidal glycoalkaloids in potatoes (Solanum tuberosum). 1)Recent studies have demonstrated that a-solanine inhibits the growth of human colon (HT29), liver (HepG2), cervical (HeLa), lymphoma (U937), and stomach (AGS and KATO III) cancer cells.3,5) a-Solanine has also been shown to induce apoptosis of human colon cancer cells through the inhibition of extracellular signal regulating kinase (ERK) phosphorylation and activation of caspase-3.6) Therefore, a-solanine may possess the potential for cancer chemotherapeutic action.Melanoma is a skin cancer that arises from the transformation of melanocytes, which are normally found in the basal layer of the epidermis. Melanoma accounts for nearly 4% of skin cancer cases but for 74% of all skin cancer mortalities. 7)Melanoma development and progression have been welldescribed as a sequential process. Following transformation of melanocytes, tumors undergo horizontal or radial initial growth phase followed by a subsequent vertical growth phase, in which melanoma cells infiltrate and invade the dermis and exhibit metastatic potential. 8,9) The conversion of benign to malignant melanoma is characterized by genetic alteration and frequent chromosomal abnormalities.10,11) Therefore, malignant melanoma has served as an excellent model for investigating the molecular changes associated with the metastatic phenotype.Cancer metastasis is a highly coordinated multistep process, in which cancer cells degrade the extracellular matrix (ECM), penetrate through the basement membrane of capillary and lymphatic vessels, intravasate, and then invade and grow in new tissue.12) The process of metastasis is promoted by expressing and secreting various proteolytic enzymes that can degrade most ECM components. Matrix metalloproteinases (MMPs), a family of Zn-dependent endopeptidases, are the major proteases participating in tumor cell migration, spreading, tissue invasion and metastasis.13) Several MMPs, such as MMP-2 and MMP-9, contribute to the process of metastasis.14,15) The activation of these enzymes enables the degradation of ECM by cancer cells, allowing their access to the vasculature, as well as their migration, and invasion into the target organ and development of cancer metastasis. 13)In addition to MMPs, the mitogen-activated protein kinase family members (MAPK) are also known to mediate metastasis. MAPK family members participate in numerous signaling cascades that play important regulatory roles in cell growth, apoptosis, differentiation, and metastasis. 16,17) The diverse MAPK members are activated in response...
The purpose of this study is to investigate the anti-metastatic effect of alpha-mangostin on phorbol 12-myristate 13-acetate (PMA)-induced matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) expressions in A549 human lung adenocarcinoma cells. Firstly, alpha-mangostin could inhibit PMA-induced abilities of the adhesion, invasion, and migration. Data also showed alpha-mangostin could inhibit the activation of alphavbeta3 integrin, focal adhesion kinase (FAK), and extracellular signal-regulated kinase1/2 (ERK1/2) involved in the downregulation the enzyme activities, protein and messenger RNA levels of MMP-2 and MMP-9 induced by PMA. Next, alpha-mangostin also strongly inhibited PMA-induced degradation of inhibitor of kappaBalpha (IkappaBalpha) and the nuclear levels of nuclear factor kappa B (NF-kappaB). Also, a dose-dependent inhibition on the binding abilities of NF-kappaB by alpha-mangostin treatment was further observed. Furthermore, reduction of FAK or ERK1/2 phosphorylation by FAK small interfering RNA (FAK siRNA) potentiated the effect of alpha-mangostin. Finally, the transient transfection of ERK siRNA significantly down-regulated the expressions of MMP-2 and MMP-9 concomitantly with a marked inhibition on cell invasion and migration. Presented results indicated alpha-mangostin is a novel, effect, anti-metastatic agent that functions by downregulating MMP-2 and MMP-9 gene expressions.
Alpha-chaconine, isolated from Solanum tuberosum Linn., is a naturally occurring steroidal glycoalkaloid in potato sprouts. Some reports demonstrated that alpha-chaconine had various anticarcinogenic properties. The aim of this study is to investigate the inhibitory effect of alpha-chaconine on lung adenocarcinoma cell metastasis in vitro. We chose the highly metastatic A549 cells, which were treated with various concentrations of alpha-chaconine to clarify the potential of inhibiting A549 cells invasion and migration. Data showed that alpha-chaconine inhibited A549 cell invasion/migration according to wound healing assay and Boyden chamber assay. Our results also showed that alpha-chaconine could inhibit phosphorylation of c-Jun N-terminal kinase (JNK) and Akt, whereas it did not affected phosphorylation of extracellular signal regulating kinase (ERK) and p38. In addition, alpha-chaconine significantly decreased the nuclear level of nuclear factor kappa B (NF-kappaB) and the binding ability of NF-kappaB. These results suggested that alpha-chaconine inhibited A549 cell metastasis by a reduction of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) activities involving suppression of phosphoinositide 3-kinase/Akt/NF-kappaB (PI3K/Akt/NF-kappaB) signaling pathway. Inhibiting metastasis by alpha-chaconine might offer a pivotal mechanism for its effective chemotherapeutic action.
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