Ethanol extract of baked Gardeniae Fructus exhibits in vitro and in vivo anti-metastatic and anti-angiogenic activities in malignant cancer cells: Role of suppression of the NF-κB and HIF-1α pathways

Im, Minju,Kim, Aeyung,Ma, Jin Yeul Lychnia 2016 International journal of oncology Vol.49 No.6

Transcriptional silencing of the inhibin-α gene in human gastric carcinoma cells.

Kim, Young Il,Shim, Jaejun,Kim, Byung-Ho,Lee, Sung Jae,Lee, Ha Kyu,Cho, Chunghee,Cho, Byung-Nam Lychnia 2012 International journal of oncology Vol.41 No.2

<P>Although inhibin was first identified as a hormone regulating pituitary FSH secretion, it was later recognized to act as a tumor suppressor in the gonad and adrenal glands. Recently, the alpha subunit of this dimeric hormone (inhibin?α) was reported to be involved in prostate tumorigenesis. To identify additional roles outside the reproductive axis, we investigated inhibin?α gene activity and subsequent cell fate in human gastric cancer cells. The results were as follows: all the gastric cancer cells had at least one of a set of abnormalities including hypermethylation of the promoter, mutation of the 5'?UTR or allelic imbalance including LOH in the inhibin?α gene. Hypermethylation of the promoter and mutation of the 5'?UTR in inhibin?α were observed in SNU?1, SNU?5 and SNU?484 cells. LOH was observed in AGS, KATO III, SNU?5, SNU?484 and SNU?668 cells. Treatment with 5?AzaC, a demethylating agent, induced demethylation of the inhibin?α promoter in the SNU?1, SNU?5 and SNU?484 cell lines, with the CpG5 site being strongly influenced by 5?AzaC. In addition, inhibin?α mRNA and protein were maintained at low levels in most of the gastric cancer cell lines. These low levels of mRNA and protein expression could be increased in most lines by treatment with 5?AzaC. These increased inhibin?α expression levels seemed to be closely associated with apoptosis and suppression of cell growth. Taken together, our results reveal that the inhibin?α gene is transcriptionally silenced in human gastric cancer cells, and that reactivation of the gene suppresses their growth characteristics. This suggests that inhibin?α may have a more general tumor suppressor activity outside the reproductive axis.</P>

Genistein, a soy phytoestrogen, prevents the growth of BG-1 ovarian cancer cells induced by 17β-estradiol or bisphenol A via the inhibition of cell cycle progression.

Hwang, Kyung-A,Kang, Nam-Hee,Yi, Bo-Rim,Lee, Hye-Rim,Park, Min-Ah,Choi, Kyung-Chul Lychnia 2013 International journal of oncology Vol.42 No.2

<P>An endocrine disrupting chemical (EDC) is a global health concern. In this study, we examined the effects of genistein (GEN) on bisphenol A (BPA) or 17β-estradiol (E2)-induced cell growth and gene alterations of BG-1 ovarian cancer cells expressing estrogen receptors (ERs). In an in vitro cell viability assay, E2 or BPA significantly increased the growth of BG-1 cells. This increased proliferative activity was reversed by treatment with ICI?182,780, a well-known ER antagonist, while cell proliferation was further promoted in the presence of propyl pyrazole triol (PPT), an ERα agonist. These results imply that cell proliferation increased by E2 or BPA was mediated by ERs, particularly ERα. BPA clearly acted as a xenoestrogen in BG-1 ovarian cancer cells by mimicking E2 action. In contrast, GEN effectively suppressed BG-1 cell proliferation promoted by E2 or BPA by inhibiting cell cycle progression. E2 and BPA increased the expression of cyclin D1, a factor responsible for the G1/S cell cycle transition. They also decreased the expression of p21, a potent cyclin-dependent kinase (CDK) inhibitor that arrests the cell cycle in G1 phase, and promoted the proliferation of BG-1 cells. As shown by its repressive effect on cell growth, GEN decreased the expression of cyclin D1 augmented by E2 or BPA. On the other hand, GEN increased the p21 expression downregulated by E2 or BPA. Collectively, our findings suggest that GEN, a dietary phytoestrogen, has an inhibitory effect on the growth of estrogen-dependent cancers promoted by E2 or BPA.</P>

Betaine inhibits in?vitro and in?vivo angiogenesis through suppression of the NF-κB and Akt signaling pathways.

Yi, Eui-Yeun,Kim, Yung-Jin Lychnia 2012 International journal of oncology Vol.41 No.5

<P>Angiogenesis is defined as the formation of new blood vessels form existing vessels surrounding a tumor. The process of angiogenesis is an important step for tumor growth and metastasis, as is inflammation. Thus, angiogenesis inhibitors that suppress inflammation have been studied as an anticancer treatment. Recently, many research groups have investigated the anti-angiogenic activity of natural compounds since some have been demonstrated to have anticancer properties. Among many natural compounds, we focused on betaine, which is known to suppress inflammation. Betaine, trimethylglycine (TMG), was first discovered in the juice of sugar beets and was later shown to be present in wheat, shellfish and spinach. In Southeast Asia, betaine is used in traditional oriental medicine for the treatment of hepatic disorders. Here, we report the anti-angiogenic action of betaine. Betaine inhibited in?vitro angiogenic cascade, tube formation, migration and invasion of human umbilical vein endothelial cells (HUVECs). Betaine also inhibited in?vivo angiogenesis in the mouse Matrigel plug assay. The mRNA expression levels of basic fibroblast growth factor (bFGF), matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) in HUVECs were decreased by betaine treatment. In addition, betaine suppressed NF-κB and Akt activation.</P>

BAI, a novel Cdk inhibitor, enhances farnesyltransferase inhibitor LB42708-mediated apoptosis in renal carcinoma cells through the downregulation of Bcl-2 and c-FLIP?(L).

Jang, Ji Hoon,Cho, Yoon Chul,Kim, Ki Ho,Lee, Kyung Seop,Lee, Jinho,Kim, Dong Eun,Park, Jun-Soo,Jang, Byeong-Churl,Kim, Shin,Kwon, Taeg Kyu,Park, Jong-Wook Lychnia 2014 International journal of oncology Vol.45 No.4

<P>Previously, we reported the potential of a novel Cdk inhibitor, 2-[1,1'-biphenyl]-4-yl-N-[5-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-1H-indazol-3-yl]acetamide (BAI) as a cancer chemotherapeutic agent. In this study, we investigated mechanisms by which BAI modulates FTI-mediated apoptosis in human renal carcinoma Caki cells. BAI synergizes with FTI to activate DEVDase, cleavage of poly ADP-ribose polymerase (PARP), and degradation of various anti-apoptotic proteins in Caki cells. BAI plus LB42708-induced apoptosis was inhibited by pretreatment with pan-caspase inhibitor, z-VAD-fmk, but not by overexpression of CrmA. The ROS scavenger, N-acetylcysteine (NAC) did not reduce BAI plus LB4270-induced apoptosis. Co-treatment of BAI and LB42708 reduced the mitochondrial membrane potential (MMP, ?ψm) in a time-dependent manner, and induced release of AIF and cytochrome?c from mitochondria in Caki cells. Furthermore, BAL plus LB42708 induced downregulation of anti-apoptotic proteins [c-FLIP?(L), c-FLIP?(s), Bcl-2, XIAP, and Mcl-1?(L)]. Especially, we found that BAI plus LB42708-induced apoptosis was significantly attenuated by overexpression of Bcl-2 and partially blocked by overexpression of c-FLIP?(L). Taken together, our results show that the activity of BAI plus LB42708 modulate multiple components in apoptotic response of human renal Caki cells, and indicate a potential as combinational therapeutic agents for preventing cancer such as renal carcinoma.</P>

Overexpression of PGC???1관 enhances cell proliferation and tumorigenesis of HEK293 cells through the upregulation of Sp1 and Acyl-CoA binding protein.

Shin, Sung-Won,Yun, Seong-Hoon,Park, Eun-Seon,Jeong, Jin-Sook,Kwak, Jong-Young,Park, Joo-In Lychnia 2015 International journal of oncology Vol.46 No.3

<P>Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha), a coactivator interacting with multiple transcription factors, regulates several metabolic processes. Although recent studies have focused on the role of PGC-la in cancer, the underlying molecular mechanism has not been clarified. Therefore, we evaluated the role of PGC-la in cell proliferation and tumorigenesis using human embryonic kidney (HEK)293 cells and colorectal cancer cells. We established stable HEK293 cell lines expressing PGC-1 alpha and examined cell proliferation, anchorage-independent growth, and oncogenic potential compared to parental HEK293 cells. To identify the molecular PGC-1 alpha targets for increased cell proliferation and tumorigenesis, the GeneFishing (TM) DEG (differentially expressed genes) screening system was used. Western blot analysis and immunofluorescence staining were performed for a regulated gene product to confirm the results. Forced expression of PGC-1 alpha in HEK293 cells promoted cell proliferation and anchorage-independent growth in soft agar. In addition, HEK293 cells that highly expressed PGC-1 alpha showed enhanced tumor formation when subcutaneously injected into the bilateral flanks of immunodeficient mice. The results of the GeneFishing DEG screening system identified one upregulated gene (Acyl-CoA binding protein; ACBP). Real-time RT-PCR, western blot analysis, and immunofluorescence staining showed that ACBP was markedly increased in HEK293 cells stably overexpressing PGC-1 alpha (PGC-1 alpha-HEK293 cells) compared to those expressing an empty vector. In PGC-1 alpha, ACBP, and specificity protein 1 (Spl) siRNA knockdown</P>

Identification of candidate biomarkers using the Experion automated electrophoresis system in serum samples from ovarian cancer patients.

Kim, Ju Hee,Kim, Yong-Wan,Kim, In-Wook,Park, Dong Chun,Kim, Yong Wook,Lee, Keun-Ho,Jang, Chun Keun,Ahn, Woong Shick Lychnia 2013 International journal of oncology Vol.42 No.4

<P>Ovarian cancer is the most common cause of disease-related death in women globally. Detection of ovarian cancer using new biomarkers is necessary for early diagnosis. To date, there have been no obvious biomarkers for ovarian cancer detection in the incipient stage. In this study, we discovered potential diagnostic serological biomarkers for ovarian cancer using the Experion automated electrophoresis system. Sera from 14 healthy women and 84 ovarian cancer patients at stages I- IV were applied to the Experion to compare the protein expression levels. To examine the protein expression pattern of Experion data, proteins in the samples were resolved using 10 and 15% sodium dodecyl sulfate-polyacrylamide gel electrophoresis and visualized by silver staining. The candidate biomarkers elevated in ovarian cancer were purified and determined using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. α-2-macroglobulin (173.7 kDa), ceruloplasmin (147 kDa), inter-α-trypsin inhibitor family heavy chain-related protein (126 kDa), C-1 inhibitor (115.2 kDa) and hemoglobin α/β (14.4 kDa were overexpressed in the ovarian cancer sera. This study documents a novel way to measure ovarian cancer or cancer-related proteins for biomarkers using the Experion assay system, which should be easily adaptable for high-throughput diagnosis to establish databases of ovarian cancer for clinical applications.</P>

Romo1 and the NF-κB pathway are involved in oxidative stress-induced tumor cell invasion.

Lee, Sora,Park, Yoon Hee,Chung, Jin Sil,Yoo, Young Do Lychnia 2015 International journal of oncology Vol.46 No.5

<P>Reactive oxygen species (ROS) are important contributors to tumor cell invasion. ROS enhanced by reactive oxygen species modulator 1 (Romol) expression has been reported to increase invasive potential and constitutive activation of nuclear factor-kappa B (NF-kappa B) in hepatocellular carcinoma (HCC). Therefore, we investigated whether constitutive NF-kappa B activation due to Romol expression is associated with breast cancer tumor cell invasion. In this study, we show that oxidative stress-induced invasion is mediated by Romol expression. The Romol-induced increase of invasive activity was blocked by an inhibitor of kappa B kinase (IKK). These tesults demonstrate that tumor cell invasion in response to oxidative stress is associated with Romol expression and the NF-kappa B signaling pathway. Romol is therefore a promising therapeutic target for diseases characterized by NF-kappa B deregulation.</P>

Induction of apoptosis and suppression of angiogenesis of hepatocellular carcinoma by HS-159, a novel phosphatidylinositol 3-kinase inhibitor.

Yun, Sun-Mi,Lee, Ju-Hee,Jung, Kyung Hee,Lee, Hyunseung,Lee, Soyoung,Hong, Sungwoo,Hong, Soon-Sun Lychnia 2013 International journal of oncology Vol.43 No.1

<P>The phosphatidylinositol 3-kinase (PI3K) pathway plays a central role in cell proliferation and survival in human cancer and is emerging as an attractive therapeutic target. In this study, we synthesized a novel PI3Kα inhibitor, HS-159 [N-(5-(3-(3-cyanophenyl)imidazo[1,2-a]pyridin-6-yl)pyridin-3-yl)benzenesulfonamide] and evaluated its anticancer effects on Huh-7 human hepatocellular carcinoma (HCC) cells. HS-159 effectively inhibited the phosphorylation of downstream PI3K effectors such as Akt, mTOR and P70S6 kinases in a dose-dependent manner. This compound also induced apoptosis and increased the fraction of apoptotic cells in the sub-G1 phase as well as the levels of cleaved PARP, caspase-3 and -9. Furthermore, HS-159 decreased the expression of hypoxia inducible factor-1α and vascular endothelial growth factor which play important roles in angiogenesis. The anti-angiogenic effect of HS-159 was confirmed by the suppression of tube formation and migration of human umbilical vein endothelial cells in vitro. Collectively, our results demonstrate that HS-159 exhibited anticancer activities including the induction of apoptosis and inhibition of angiogenesis by blocking the PI3K/Akt pathway in Huh-7 cells. Therefore, we suggest that this drug may be potentially used for targeted HCC therapy.</P>

Apoptosis induction of human prostate carcinoma cells by cordycepin through reactive oxygen species?mediated mitochondrial death pathway.

Lee, Hye Hyeon,Park, Cheol,Jeong, Jin-Woo,Kim, Min Jeong,Seo, Min Jeong,Kang, Byoung Won,Park, Jeong Uck,Kim, Gi-Young,Choi, Byung Tae,Choi, Yung Hyun,Jeong, Yong Kee Lychnia 2013 International journal of oncology Vol.42 No.3

<P>Cordycepin is the main functional component of Cordyceps militaris, which has been widely used in oriental traditional medicine. This compound has been shown to possess many pharmacological properties, such as enhancing the body's immune function, and anti-inflammatory, anti-aging and anticancer effects. In the present study, we investigated the apoptotic effects of cordycepin in human prostate carcinoma cells. We found that treatment with cordycepin significantly inhibited cell growth by inducing apoptosis in PC-3 cells. Apoptosis induction of PC-3 cells by cordycepin showed correlation with proteolytic activation of caspase-3 and -9, but not caspase-8, and concomitant degradation of poly (ADP-ribose) polymerases, collapse of the mitochondrial membrane potential (MMP). In addition, cordycepin treatment resulted in an increase of the Bax/Bcl-2 (or Bcl-xL) ratio, downregulation of inhibitor of apoptosis protein (IAP) family members, Bax conformational changes, and release of cytochrome c from the mitochondria to the cytosol. The cordycepin-induced apoptosis was also associated with the generation of intracellular reactive oxygen species (ROS). However, the quenching of ROS generation with antioxidant N-acetyl-L-cysteine conferred significant protection against cordycepin-elicited ROS generation, disruption of the MMP, modulation of Bcl-2 and IAP family proteins, caspase-3 and -9 activation and apoptosis. This indicates that the cellular ROS generation plays a pivotal role in the initiation of cordycepin-triggered apoptotic death. Collectively, our findings suggest that cordycepin is a potent inducer of apoptosis of prostate cancer cells via a mitochondrial-mediated intrinsic pathway and that this agent may be of value in the development of a potential therapeutic candidate for both the prevention and treatment of cancer.</P>