SOCS1 induced by NDRG2 expression negatively regulates STAT3 activation in breast cancer cells

Park, Yongjin,Shon, Soo-Kyung,Kim, Aeyung,Kim, Keun Il,Yang Young,Cho, Dae Ho,Lee, Myeong-Sok,Lim, Jong-Seok Research Institute of Women's Health Sookmyung Wom 2007 WOMEN And HEALTH Vol.3 No.1

Although NDRG2 inactivation has recently been found to have an important role in some tumorigenesis, its role in intracellular signal transduction pathways remains poorly defined. In the present study, we demonstrate that NDRG2 overexpression in malignant breast cancer cells specifically inhibits Akt phosphorylation and induces phosphorylation of p38 MAP kinase and SAPK/JHK. In addition, we investigated whether NDRG2 expression affects JAK/STAT- or mitogen-activated protein kinase-mediated signal activation. JAK2 or STAT3 activation in both resting and IGF-stimulating cells was remarkably inhibited by NDRG2 expression. Furthermore, NDRG2 has been found to highly up-regulate the expression level of SOCS1 mRNA and protein. We have found that NDRG2 was able to regulate cytokine signaling in breast cancer cells through the regulation of SOCS1 expression. Finally, inhibition of p38 MAPK activity blocked the induction of SOCS1 expression by NDRG2, resulting in the recovery of STAT3 phosphorylation leve.l Together, these data demonstrate that NDRG2 expression in breast cancer cells is able to inhibit STAT3 activation via SOCS1 induction in a p38 MAPK dependent manner, implicating NDRG2 as a growth inhibitory gene in signal transduction pathways of breast tumor cells.

Methyselenol Generated from Selenomethionine and Methioninase Induces Apoptosis and Blocks Metastasis of Melanoma

Kim, Aeyung,Lim, Jong-Seok Research Institute of Women's Health Sookmyung Wom 2007 WOMEN And HEALTH Vol.3 No.2

Selenium, an essential trace element for animal and human, has been proven to maintain good health and shown to prevent several diseases. The effects of selenium compounds on tumor cell proliferation and onset of cancer are dependent on the dose and chemical composition. Current experimental evidence indicates that methylselenol (CH₃SeH), a selenium metabolite, is responsible for the dietary chemoprevention of cancers. Studies have shown that interactions between cancer cells and the extracellular matrix (ECM) are critical for the survival and invasion of metastatic cancer cells including melanoma. Despite considerable public interest in the beneficial effects of selenium compounds for melanoma chemoprevention, limited information is currently available on the molecular targets or signaling mechanisms underlying the anti-cancer effects. In this review, we introduce the anti-cancer mechanism by methylselenol based on our recent experimental data. In our studies, it was shown that methylselenol generated from selenomethionine (SeMet) plus methioninase (METase) exerts an anti-cancer effect on B16F10 melanoma cells by modulating integrin expression, altering adhesion capacity, and inducing caspase-mediated apoptosis. Furthermore, activation of p38, PKC-δ, and NF-κB was a prerequisite fur the down-regulation of integrin expression, followed by detachment-mediated apoptosis. In addition to the induction of apoptosis by the supra-nutritional level of methylselenol, non-toxic low level of methylselenol inhibited the invasive potential of B16F10 melanoma cells, particularly in association with the modulation of integrin expression. From these results, it is suggested that decreased integrin expression by methylselenol is associated with the induction of apoptosis and the inhibition of metastasis of melanoma in mice.

Adiponectin as a Negative Regulator in Breast Cancer

Kim, Kun-Yong,Yang, Young Research Institute of Women's Health Sookmyung Wom 2007 WOMEN And HEALTH Vol.3 No.2

Adipocytes secrete a variety of growth factors and cytokines, termed collectively as adipokines, including adiponectin, leptin, and vascular endothelial growth factor (VEGF). Moreover, many of the aforementioned adipokines have been shown to differentially modulate cellular differentiation, apoptosis, proliferation, and angiogenesis. It is generally accepted that dysregulation of adipokines may represent one of the causal links between obesity and insulin resistance/diabetes. Epidemiological studies have established that obesity represents a significant risk factor for the development of cancer and most of adipokines significantly potentiate the growth of cancer cell in vitro, but adiponectin appears to have an opposite effect. Although the exact mechanism of this relationship remains to be determined, multiple recent studies have indicated that adiponectin significantly influence the growth and proliferation of malignant cells. Here we review current knowledge about relationship of adiponectin and breast cancer risk. Most of the studies indicated that low adiponectin plasma level is an independent risk (actor for breast cancer disease and breast tumors in woman with low se겨m adiponectin are more likely to show a biologically aggressive phenotype. Moreover, it has been known that adiponectin inhibits the proliferation and metastasis of breast cancer cells in vivo and in vitro.

Breast Cancer Metastasis to Bone : Interactions between Tumor and Bone

Yoon, Sun Young,Cho, Daeho Research Institute of Women's Health Sookmyung Wom 2007 WOMEN And HEALTH Vol.3 No.2

Breast cancer has a propensity to metastasize to bone, which has a plenty of growth factors and cell types that support a hospitable environment for breast cancer growth, and causes osteolysis and abnormal new bone formation leading to bone pain and fracture. Bone metastases are present in 80% of patients with advanced stage of breast cancer and the communication between breast cancer cells and bone microenvironment contributes to the development of bone metastases. Otherwise, breast cancer cells express chemokine receptors, adhesion molecules, bone-resorbing and forming factors that render bone metastasis. After breast cancer cells enter the bone, tumor-secreted factors act on bone cells and other cells within the bone including stem cells, hematopoietic cells, mesenchymal cells, and endothelial cells, causing them to secrete various factors that in turn affect on tumor cells. The clinical consequences of bone metastasis are bone pain, fractures, nerve compression, and hypercalcemia, caused increased morbidity and mortality in patients with breast cancer. Bisphosphates are common small molecule therapeutics far the treatment of patients with breast cancer bone metastasis. Also antiestrogen and aromatase inhibitors may be a helpful treatment to the disease. This review focused on the overall molecular mechanisms between breast cancer cells and bone microenvironment.

Identification of Phosphotyrosine Binding Domain-Containing Proteins as Novel Downstream Targets of the EphA8 Signaling Function

Shin, Jongdae,Gu, Changkyu,Park, Eunjeong,Park, Soochul Research Institute of Women's Health Sookmyung Wom 2007 WOMEN And HEALTH Vol.3 No.1

Eph receptors and ephrins have been implicated in a variety of cellular processes, including morphology and motility, because of their ability to modulate intricate signaling networks. Here we show that the phosphotyrosine binding (PTB) domain-containing proteins AIDA-lb and Odin are tightly associated with the EphA8 receptor in response to ligand stimulation. Both AIDA- lb and Odin belong to the ankyrin repeat and sterile alpha motif domain-containing (Anks) protein family. The PTB domain of Anks family proteins is crucial for their association with the juxtamembrane domain of EphA8, whereas EphA8 tyrosine kinase activity is not required far this protein-protein interaction. In addition, we found that Odin is a more physiologically relevant partner of EphA8 in mammalian cells. Interestingly, overexpression of the Odin PTB domain alone attenuated EphA8-mediated inhibition of cell migration in HEK293 cells, suggesting that it acts as a dominant-negative mutant of the endogenous Odin protein. More importantly, small interfering RNA-mediated Odin silencing significantly diminished ephrinA5-induced EphA8 signaling effects, which inhibit cell migration in HEK293 cells and retract growing neurites of Neuro2a tells. Taken together, our findings support a possible function far Anks family proteins as scaffolding proteins of the EphA8 signaling pathway.

The Biomarkers of Breast Cancer

Choi, Suh Hee,Park, Jong Hoon Research Institute of Women's Health Sookmyung Wom 2007 WOMEN And HEALTH Vol.3 No.2

Breast cancer is the most common malignant disease in the worldwide and is the leading cause of cancer death. Among women worldwide, breast cancer is the most cause of cell death. The tumor marker (also called a biomarker) is a substance found in higher than normal amounts in the blood, urine, or body tissues of people with certain kinds of cancer. Many kinds of breast cancer cell biomarkers are discovered so far. The biomarkers of breast cancer can classify according to type and function such as screening, diagnosis, prognosis, monitoring etc. This review summarizes current data of the clinical biomarkers in breast cancer cell.

Screening of Korea medicinal plants for possible osteoclastogenesis effects in vitro

Youn, Yu Na,Lim, Erang,Lee, Nari,Kim, Young Seop,Koo, Min Seon,Choi, Soon Young Research Institute of Women's Health Sookmyung Wom 2007 WOMEN And HEALTH Vol.3 No.1

Bone undergoes continuous remodeling through bone formation and resorption, and maintaining the balance for skeletal rigidity. Bone resorption and loss are generally attributed to osteoclasts. Differentiation of osteoclasts is regulated by receptor activator of nuclear factor NF-κB ligand (RANKL), a member of tumor necrosis factor family When the balance is disturbed, pathological bone abnormality ensues. Through the screening of traditional Korean medicinal plants, the effective molecules for inhibition and stimulation of RANKL-induced osteoclast differentiation in mouse bone marrow macrophages were identified. Among 222 methanol extracts, of medicinal plants, 10 samples exhibited ability to induce osteoclast differentiation. These include Dryobalanoops aromatica, Euphoria longana, Lithospermum erythrorhizon, Prunus mume, Prunus nakaii and Polygonatum odoratum. In contrast, Ailanthus altissima, Curcuma longa, Solanum nigrum, Taraxacum platycarpa, Trichosanthes kirilowii, and Daphne genkwa showed inhibitory effects in RANKL induced osteoclast differentiation.

Engineering lacZ Reporter Gene into an ephA48 Bacterial Artificial Chromosome Using a Highly Efficient Bacterial Recombination System

Kim, Yujin,Song, Eunsook,Choi, Soonyoung,Park, Soochul Research Institute of Women's Health Sookmyung Wom 2007 WOMEN And HEALTH Vol.3 No.1

In this report, we describe an optimized method for generation of ephA8 BAC transgenic mice expressing the lacZ reporter gene under ephA8 regulatory sequences. First, we constructed a targeting vector that carries a 1.2 kb ephA8 DNA upstream of its first exon, a fαcf expression cassette, a kanamycin cassette, and a 0.7 kb ephA8 DNA downstream of its first exon. Second, the targeting vector was electroporated into cells containing the ephA8 BAC and pKOBEGA, in which recombinases induce a homologous recombination between the ephA8 BAC DNA and the targeting vector. Third, the FLP plasmid expressing the Flipase was electroporated into these bacteria to eliminate a kanamycin cassette from the recombinant BAC DNA. The appropriate structures of the modified ephA8 BAC DNA were confirmed by Southern analysis. Finally, BAC transgenic mouse embryos were generated by pronuclear injection of the recombinant BAC DNA. Whole mount X-gal staining revealed that the lacZ reporter expression is restricted to the anterior region of the developing midbrain in each transgenic embryo. These results indicate that the ephA8 BAC DNA contains most, if not all, regulatory sequences to direct temporal and spatial expression of the fαof gene in vivo.

비스테로이드성 항염증제, 술린닥이 유방암세포에 미치는 항암효과

서아미,이명석 Research Institute of Women's Health Sookmyung Wom 2007 WOMEN And HEALTH Vol.3 No.2

비스테로이드성 항염증제(Non-Steroidal Anti-Inflammatory Drug, NSAID)는 사이클로옥시제나제(cyclooxygenase)를 억제시켜 프로스타글란딘(prostaglandin) 생성을 억제시킴으로써 염증과 고통을 완화시키는 역할을 한다. 최근에 NSAID는 이러한 염증이나 고통완화뿐만 아니라 항암의 효과를 가진 것으로 밝혀지고 있다. NSAID는 세포자살을 관여하는 유전자의 발현을 조절하는 NF-κB(Nuclear factor κB)의 활성을 억제하거나, 세포자살을 조절하는 p38과 JNK1을 조절하여 다양한 암세포에서 항암작용을 나타내고 있다. 특히 대장암이나 전립선암에서는 NSAID의 한 종류인 술린닥(sulindac)과 다른 항암제 또는 COX-2(cyclooxygenase-2) 억제제를 함께 처리함으로써 치료의 효과를 보고 있다고 한다. 그러나 유방암에서의 치료는 아직 미미한 실정이다. 따라서 여기에서는 NSAID의 한 종류인 술린닥이 유방암세포의 치료에 사용될 수 있는지의 여부에 대해 논의하고자 한다.

CSSP2 : An improved method for predicting contact-dependent secondary structure propensity

Yoon, Sukjoon,Welsh, Willian J,Jung, Heeyoung,Yoo, Young Do Research Institute of Women's Health Sookmyung Wom 2007 WOMEN And HEALTH Vol.3 No.1

The calculation of contact-dependent secondary structure propensity (CSSP) has been reported to sensitively detect non-native β-strand propensities in the core sequences of amyloidogenic proteins. Here we describe a noble energy-based CSSP method implemented on dual artificial neural networks that rapidly and accurately estimate the potential for the non-native secondary structure formation in local regions of protein sequences. In this method, we attempted to quantify long-range interaction patterns in diverse secondary structures by potential energy calculations and decomposition on a pairwise per-residue basis. The calculated energy parameters and seven-residue sequence information were used as inputs for artificial neural networks (ANNs) to predict sequence potential for secondary structure conversion. The trained single ANN using the >(i, i ± 4) interaction energy Parameter exhibited 74% accuracy in predicting the secondary structure of test sequences in their native energy state, while the dual ANN-based predictor using (i, i ± 4) and >(i, i ± 4) interaction energies showed 83% prediction accuracy. The present method provides a simple and accurate tool for predicting sequence potential for secondary structure conversions without using 3D structural information.