Metastasis is a major cause of cancer-related mortality in patients with gastric cancer. Ursolic acid, a pentacyclic triterpenoid compound derived from medicinal herbs, has been demonstrated to exert anticancer effects in various cancer cell systems. However, to the best of our knowledge, the inhibitory effect of ursolic acid on the invasive phenotype of gastric cancer cells has yet to be reported. Therefore, the aim of the present study was to investigate the effect of ursolic acid on the invasiveness of SNU-484 human gastric cancer cells. Ursolic acid efficiently induced apoptosis, possibly via the downregulation of B-cell lymphoma 2 (Bcl-2), the upregulation of Bcl-2-associated X protein and the proteolytic activation of caspase-3. Furthermore, the activation of p38 mitogen-activated protein kinase and c-Jun N-terminal kinase was increased by the administration of ursolic acid. In addition, ursolic acid significantly suppressed the invasive phenotype of the SNU-484 cells and significantly decreased the expression of matrix metalloproteinase (MMP)-2, indicating that MMP-2 may be responsible for the anti-invasive activity of ursolic acid. Taken together, the results of the present study demonstrate that ursolic acid induces apoptosis and inhibits the invasive phenotype of gastric cancer cells; therefore, ursolic acid may have a potential application as a chemopreventive agent to prevent the metastasis of gastric cancer or to alleviate the process of metastasis.

Triple-negative breast cancer (TNBC) is one of the most aggressive types of breast cancer, and there is no effective therapeutic target to date. Natural killer (NK) cells are functionally diverse lymphocytes that recognize and kill cancer cells. Although it is clear that NK cells exert antitumor activity in the tumor microenvironment, their role in the aggressive progression of TNBC has not been elucidated in detail. In the present study, we investigated the effect of NK cells on MDA-MB-231 TNBC cells using an indirect co-culture system. The invasive phenotype of MDA-MB-231 cells was significantly inhibited by co-culture with NK cells. Notably, the expression of urokinase-type plasminogen activator (uPA) was markedly reduced by NK cells. Cytokine array analysis showed that the levels of interleukin (IL)-10, IL-6, IL-8, C-C motif ligand (CCL)5, and CCL2 were increased in conditioned media from the co-cultured cells. Among these cytokines, IL-6 played a crucial role in the NK cell-induced uPA downregulation and inhibition of the invasive phenotype of MDA-MB-231 cells and Hs578T cells. We analyzed the Gene Expression Profiling Interactive Analysis database for correlations between IL-6 and uPA with the overall survival of breast cancer patients. The Kaplan-Meier survival analysis revealed that a low IL-6/uPA ratio was associated with the poor survival of breast cancer patients, suggesting it as an important factor for determining the overall survival of breast cancer patients. Taken together, our findings demonstrate that NK cells in the tumor microenvironment inhibit the invasiveness of TNBC cells through the IL-6-mediated inhibition of uPA.

Pyridazine derivatives R 0500Synthesis of Novel Allylthio Heterocyclo(or aryl)alkylaminopyridazines and Their Anticancer Activity Against SK-Hep-1 Cells. -The title compounds (III) show antiproliferative activities against SK-Hep-1 human liver cancer cells in MTT assays. Thus, they are promising candidates for the chemotherapy of hepatocellular carcinomas. Compounds (IIIc) and (IIIi) exhibit higher potencies for inhibiting the growth of hepatocellular carcinoma cells than K6. -(LEE, M.-S.; KIM, E.-S.; MOON, A.; PARK*, M.-S.; Bull. Korean Chem. Soc. 30 (2009) 1, 83-91; Coll. Pharm., Duksung Women's Univ., Seoul 132-714, S. Korea; Eng.) -H. Toeppel 28-141

Ras mutations have been frequently observed in human cancer. Although there is a high degree of similarity between Ras isomers, they display preferential coupling in specific cancer types. The binding of Ras to the plasma membrane is essential for its activation and biological functions. The present study elucidated Ras isoform-specific interactions with the membrane and their role in Ras-mediated biological activities.We investigated the role of a lipid raft protein flotillin-1 (Flot-1) in the activations of Ras. We found that Flot-1 was co-localized with H-Ras, but not with N-Ras, in lipid rafts of MDA-MB-231 human breast cells. The amino-terminal hydrophobic domain (1-38) of Flot-1 interacted with the hypervariable region of H-Ras. The epidermal growth factor-stimulated activation of H-Ras required Flot-1 which was not necessary for that of N-Ras in breast cancer cells. Flot-1 interacted with son of sevenless (SOS)-1, which promotes the conversion of Ras-bound GDP to GTP. Notably, Flot-1 was crucial for the interaction between SOS1 and H-Ras/K-Ras in breast and pancreatic cancer cells. Stable knockdown of Flot-1 reduced the in vivo metastasis in a mouse xenograft model with human breast carcinoma cells. A tissue microarray composed of 61 human pancreatic cancer samples showed higher levels of Flot-1 expression in pancreatic tumor tissues compared to normal tissues, and a correlation between K-Ras and Flot-1. Taken together, our findings suggest that Flot-1 may serve as a membrane platform for the interaction of SOS1 with H-Ras/K-Ras in human cancer cells, presenting Flot-1 as a potential target for Ras-driven cancers.

Although mounting evidence suggests a role for G12 proteins, Gα12 and Gα13, in tumor progression, a direct role of G12 proteins has not been determined. This study aims to elucidate the molecular mechanism for tumorigenic/invasive potential of Gα12/13 in MCF10A human breast epithelial cells. Here we report, for the first time, that Gα12/13 induce upregulation of matrix metalloproteinase(MMP)‐2 leading to the invasive/migratory phenotypes in MCF10A cells. We further show that p53 is an important transcription factor for induction of MMP‐2 transcriptional activation by Gα12/13. Using human breast tissue samples, we demonstrate that the expression levels of Gα12 and MMP‐2 are strongly correlated with the pathogenically diagnosed cancer. To elucidate a causal relationship between inflammation and the control of invasiveness of breast cells, the effect of the inflammatory lipid sphingosine‐1‐phosphate(S1P) on the regulation of invasive/migratory phenotypes of MCF10A cells was investigated. S1P causes induction of MMP‐9 in vitro/in vivo, and enhances invasion/migration which is triggered by S1P3‐Gαq coupling. Activation of PLC‐β4 and intracellular Ca2+ release are required for S1P‐induced MMP‐9 upregulation. Taken together, this study elucidated the role of G12 proteins and S1P in regulating processes for MMP expression and malignant phenotypic conversion of breast cells.