Detection of hepatocyte growth factor/scatter factor receptor (c-Met) in axillary drainage after operations for breast cancer using reverse transcriptase–polymerase chain reaction

Background  

The diverse biological effects of hepatocyte growth factor/scatter factor (HGF/SF) are mediated by c-Met, which is preferentially expressed on epithelial cells. Met signaling has a role in normal cellular activities, and may be associated with the development and progression of malignant processes. In this study we examined whether Met can be detected in the axillary drainage from patients who underwent conservative operations for breast cancer, and its prognostic significance.     

Efficacy of c-Met inhibitor for advanced prostate cancer

Background  

Aberrant expression of HGF/SF and its receptor, c-Met, often correlates with advanced prostate cancer. Our previous study showed that expression of c-Met in prostate cancer cells was increased after attenuation of androgen receptor (AR) signalling. This suggested that current androgen ablation therapy for prostate cancer activates c-Met expression and may contribute to development of more aggressive, castration resistant prostate cancer (CRPC). Therefore, we directly assessed the efficacy of c-Met inhibition during androgen ablation on the growth and progression of prostate cancer.     

Breast tumor kinase and extracellular signal-regulated kinase 5 mediate Met receptor signaling to cell migration in breast cancer cells

Introduction  

Breast tumor kinase (Brk/protein tyrosine kinase 6 (PTK6)) is a nonreceptor, soluble tyrosine kinase overexpressed in the majority of breast tumors. Previous work has placed Brk downstream of epidermal growth factor receptor (ErbB) activation and upstream of extracellular signal-regulated kinase 5 (ERK5) and p38 mitogen-activated protein (MAP) kinases. Herein we investigate the regulation of Brk kinase activity and cell migration in response to treatment of keratinocytes (HaCaT cells) and breast cancer cell lines (MDA-MB-231 and T47D cells) with hepatocyte growth factor (HGF) and macrophage stimulating protein (MSP), peptide ligands for Met and Ron receptors, respectively.     

The polyphenol epigallocatechin‐3‐gallate affects lipid rafts to block activation of the c‐Met receptor in prostate cancer cells

The HGF/c‐Met pathway is an important regulator of signaling pathways responsible for invasion and metastasis of most human cancers, including prostate cancer. Exposure of DU145 prostate tumor cells to HGF stimulates the PI3‐kinase and MAPK pathways, leading to increased scattering, motility, and invasion, which was prevented by the addition of EGCG. EGCG acted at the level of preventing phosphorylation of tyrosines 1234/1235 in the kinase domain of the c‐Met receptor without effecting dimerization. HGF‐induced changes were independent of the formation of reactive oxygen species, suggesting that EGCG functioned independent of its antioxidant ability. ECG, another tea polyphenol, was as effective as EGCG, while EGC and EC were less effective. EGCG added up to 4 h after the addition of HGF still blocked cell scattering and reduced the HGF‐induced phosphorylation of c‐Met, Akt, and Erk, suggesting that EGCG could act both by preventing activation of c‐Met by HGF and by attenuating the activity of pathways already induced by HGF. HGF did not activate the MAPK and PI3‐K pathways in cells treated with methyl‐β‐cyclodextrin (mCD) to remove cholesterol. Furthermore, subcellular fractionation approaches demonstrated that only phosphorylated c‐Met accumulated in Triton X‐100 membrane insoluble fractions, supporting a role for lipid rafts in regulating c‐Met signaling. Finally, EGCG treatment inhibited DiIC₁₆ incorporation into membrane lipid ordered domains, and cholesterol partially inhibited the EGCG effects on signaling. Together, these results suggest that green tea polyphenols with the R1 galloyl group prevent activation of the c‐Met receptor by altering the structure or function of lipid rafts. © 2010 Wiley‐Liss, Inc.     

Genistein inhibits radiation-induced activation of NF-κB in prostate cancer cells promoting apoptosis and G2/M cell cycle arrest

Background  

New cancer therapeutic strategies must be investigated that enhance prostate cancer treatment while minimizing associated toxicities. We have previously shown that genistein, the major isoflavone found in soy, enhanced prostate cancer radiotherapy in vitro and in vivo. In this study, we investigated the cellular and molecular interaction between genistein and radiation using PC-3 human prostate cancer cells.     

Reduced tumor growth in vivo and increased c-Abl activity in PC3 prostate cancer cells overexpressing the Shb adapter protein

Background  

Induction of apoptosis is one strategy for treatment of prostate cancer. The Shb adapter protein has been found to regulate apoptosis in various cell types and consequently human prostate cancer 3 (PC3) cells were transfected to obtain cells overexpressing Shb in order to increase our understanding of the mechanisms regulating PC3 cell apoptosis.     

The HGF/SF antagonist NK4 reverses fibroblast- and HGF-induced prostate tumor growth and angiogenesis in vivo

Our study examined the in vitro and in vivo responses of a newly discovered HGF/SF antagonist, NK4, on HGF/SF-promoted growth of human prostate cancer cells (PC-3). Nude mice were s.c. injected with either PC-3- and/or HGF/SF-producing fibroblasts (MRC5), and tumor size was measured over a 4-week period. rh-HGF/SF and/or NK4 were introduced by osmotic minipumps. An in vitro study found that NK4 significantly suppressed HGF/SF-induced invasion (HGF/SF; p < 0.01 vs. HGF/SF+NK4) and migration (HGF/SF; p < 0.05 vs. HGF/SF+NK4). Similarly, NK4 also suppressed the invasion (MRC5; p < 0.01 vs. MRC5+NK4) and migration (MRC5; p < 0.05 vs. MRC5+NK4) induced by MRC5 cells. NK4 also suppressed HGF/SF- and MRC5-induced tyrosine phosphorylation of the HGF/SF receptor Met as assessed by immunoprecipitation. Using a nude mouse model, prostate tumor volume (mm(3)) was significantly increased in both HGF/SF- (HGF/SF; p < 0.05 vs. control) and MRC5- (MRC5; p < 0.01 vs. control) treated groups compared to the control. In contrast, NK4 alone significantly reduced the growth of prostate tumors (NK4; p < 0.01 vs. control). In addition, NK4 also suppressed both HGF/SF- (HGF/SF; p < 0.01 vs. HGF/SF+NK4) and MRC5- (MRC5; p < 0.05 vs. MRC5+NK4) induced tumor growth in vivo by significantly reducing (p < 0.05) the degree of tumor angiogenesis using a recently discovered family of tumor endothelial markers (TEMs) by Q-RT-PCR analysis. In conclusion, NK4 suppresses both HGF/SF- and MRC5-induced invasion/migration of PC-3 cells in vitro. Furthermore, the HGF/SF antagonist NK4 significantly reduces prostate tumor growth in vivo by inhibiting the degree of tumor angiogenesis as determined by TEM-1 and TEM-8. Finally, our study provides evidence of the therapeutic potential of NK4 in prostate cancer development by antagonising HGF/SF-mediated events.     

Effects on proliferation and migration of the human colon carcinoma cell line SW620 by silencing of hepatocyte growth factor expression

Objective  

Hepatocyte growth factor (HGF) expression is closely related to the progression and poor prognosis of colorectal cancer patients. In this study, we investigated the effects on proliferation and migration of the human colon carcinoma cell line SW620 by silencing HGF expression.     

Membrane androgen receptor activation triggers down-regulation of PI-3K/Akt/NF-kappaB activity and induces apoptotic responses via Bad,FasL and caspase-3 in DU145 prostate cancer cells

Background  

Recently we have reported membrane androgen receptors-induced apoptotic regression of prostate cancer cells regulated by Rho/ROCK/actin signaling. In the present study we explored the specificity of these receptors and we analyzed downstream effectors controlling survival and apoptosis in hormone refractory DU145-prostate cancer cells stimulated with membrane androgen receptor-selective agonists.     

Oncolytic targeting of androgen-sensitive prostate tumor by the respiratory syncytial virus (RSV): consequences of deficient interferon-dependent antiviral defense

Background  

Oncolytic virotherapy for cancer treatment utilizes viruses for selective infection and death of cancer cells without any adverse effect on normal cells. We previously reported that the human respiratory syncytial virus (RSV) is a novel oncolytic virus against androgen-independent PC-3 human prostate cancer cells. The present study extends the result to androgen-dependent prostate cancer, and explores the underlying mechanism that triggers RSV-induced oncolysis of prostate cancer cells.     

A Smac-mimetic sensitizes prostate cancer cells to TRAIL-induced apoptosis via modulating both IAPs and NF-kappaB

Background  

Although tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising agent for human cancer therapy, prostate cancer still remains resistant to TRAIL. Both X-linked inhibitor of apoptosis (XIAP) and nuclear factor-kappaB function as key negative regulators of TRAIL signaling. In this study, we evaluated the effect of SH122, a small molecule mimetic of the second mitochondria-derived activator of caspases (Smac), on TRAIL-induced apoptosis in prostate cancer cells.     

Interaction between human-breast cancer metastasis and bone microenvironment through activated hepatocyte growth factor/Met and β-catenin/Wnt pathways

To clarify the reciprocal interaction between human-breast cancer metastatic cells and bone microenvironment, we studied the influence of HGF/Met system on a proposed-prognostic marker of aggressiveness, the β-catenin/Wnt pathway. For in vitro and in vivo experiments we used 1833-bone metastatic clone, derived from human-MDA-MB231 cells. In osteolytic bone metastases and in metastatic cells, Met was expressed in nuclei and at plasma membrane, and abnormally co-localised at nuclear level with β-catenin and the tyrosine phosphorylated c-Src kinase. Thus, in 1833 cells nuclear-Met COOH-terminal fragment and β-catenin-TCF were constitutively activated, possibly by receptor and non-receptor tyrosine kinases. The activity of the gene reporter TOPFLASH (containing multiple TCF/LEF-consensus sites) was measured, as index of β-catenin functionality. In 1833 cells, human and mouse HGF increased Met and β-catenin tyrosine phosphorylation and expression in nuclear and perinuclear compartments, β-catenin nuclear translocation via Kank and TOPFLASH transactivation. Human HGF was autocrine/intracrine in bone metastasis, and mouse HGF originating from the adjacent host-bone marrow, was found inside the metastatic nuclei. Parental MDA-MB231 cell nuclei did not show functional β-catenin, for TCF-transactivating activity, and the regulation by HGF. Our study highlighted the importance of the metastasis-stroma interaction in human-breast cancer metastatisation and first identified the HGF/nuclear Met/phospho-c-Src/β-catenin-TCF/Wnt pathway as a potential-therapeutic target to delay establishment/progression of bone metastases by affecting the aggressive phenotype.     

Isoalantolactone induces apoptosis through ROS-mediated ER stress and inhibition of STAT3 in prostate cancer cells

Background

Prostate cancer is one of the most commonly diagnosed cancers in men worldwide. Currently available therapies for metastatic prostate cancer are only marginally effective. Therefore, new therapeutic agents are urgently needed to improve patient outcome. Isoalantolactone (IATL), an active sesquiterpene naturally present in many vegetables and medicinal plants, is known to induce cell death and apoptosis in various cancer cell lines. Nevertheless, antitumor mechanisms initiated by IATL in cancer cells have not been fully defined.

Methods

Cell apoptosis and cellular ROS levels were analyzed by flow cytometry. Western blot and qRT-PCR were used to analyze the protein and mRNA levels of indicated molecules, respectively. Nude mice xenograft model was used to test the effects of IATL on prostate cancer cell growth in vivo.

Results

In this study, we found that IATL dose-dependently inhibited cancer cell growth and induced apoptosis in PC-3 and DU145 cells. Mechanistically, our data found that IATL induced reactive oxygen species (ROS) production, resulting in the activation of endoplasmic reticulum stress pathway and eventually cell apoptosis in prostate cancer cells. IATL also decreased the protein expression levels of p-STAT3 and STAT3, and the effects of IATL were reversed by pretreatment with N-acetyl-L-cysteine (NAC). In vivo, we found that IATL inhibited the growth of prostate cancer xenografts without exhibiting toxicity. Treatment of mice bearing human prostate cancer xenografts with IATL was also associated with induction of ER stress and inhibtion of STAT3.

Conclusion

In summary, our results unveil a previously unrecognized mechanism underlying the biological activity of IATL, and provide a novel anti-cancer candidate for the treatment of prostate cancer.

     

Intake of heterocyclic aromatic amines and the risk of prostate cancer in the EPIC-Heidelberg cohort

Background  

Heterocyclic amines (HCA) are positively associated with prostate cancer risk in animal models. Because of mostly inconsistent results of epidemiological studies, we examined the association between intake of HCA and prostate cancer risk.     

Vav3 oncogene activates estrogen receptor and its overexpression may be involved in human breast cancer

Background  

Our previous study revealed that Vav3 oncogene is overexpressed in human prostate cancer, activates androgen receptor, and stimulates growth in prostate cancer cells. The current study is to determine a potential role of Vav3 oncogene in human breast cancer and impact on estrogen receptor a (ERα)-mediated signaling axis.     

IL-6 signaling by STAT3 participates in the change from hyperplasia to neoplasia in NRP-152 and NRP-154 rat prostatic epithelial cells

Background  

STAT3 phosphorylation is associated with the neoplastic state in many types of cancer, including prostate cancer. We investigated the role of IL-6 signaling and phosphorylation of STAT3 in 2 rat prostatic epithelial lines. NRP-152 and NRP-154 cells were derived from the same rat prostate, yet the NRP-152 cells are not tumorigenic while the NRP-154 cells are tumorigenic. These lines are believed to represent 2 of the stages in the development of prostate cancer, hyperplasia and neoplasia. Differences in signaling pathways should play a role in the 2 phenotypes, hyperplastic and neoplastic.