bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2571: The effect of 15-deoxy-α12,14-prostaglandin J2 on osteolytic bone metastasis by breast cancer cells
Authors: Kim Ki-Rim , Chung Won-Yoon , Park Kwang-Kyun 
Published: August 2012

Abstract
The majority of patients dying from cancer of the breast or prostate have metastases to bone. Bone is a dynamic tissue and metastatic breast cancer cells indirectly induce osteoclast-mediated bone resorption by secreting osteolytic factors, resulting in the increase of bone destruction. 15-deoxy-α12,14-prostaglandin J2 (15d-PGJ2), an endogenous ligand for peroxisome proliferator-activated receptor-α, is the electrophilic cyclopentenone prostaglandin as one of the terminal products of the cyclooxygenase-2-catalyzed reactions. Through the post-translational modification of redox and inflammatory signaling molecules, this prostaglandin exerts various biological actions, such as potent anti-inflammatory, anti-proliferative, anti-fibrotic, and apoptotic activities. In particular, 15d-PGJ2 has been known to exhibit anti-tumor effects in a variety of cancers. This study explores the in vitro and in vivo effect of 15d-PGJ2 on osteolytic bone metastasis by breast cancer cells. 15d-PGJ2 inhibited the migration and invasion of MDA-MB-231 metastatic human breast cancer cells, in a dose-dependent manner. Treatment with 15d-PGJ2 inhibited osteoclast formation and reduced pit formation by osteoclast activity in receptor activator of the NF-κB ligand (RANKL)-treated mouse bone marrow macrophages (BMMs). In differentiated osteoclasts, the activities of matrix metalloproteinases (MMPs) and cathepsin K markedly decreased by 15d-PGJ2 treatment. Furthermore, we inoculated MDA-MB-231 cells into the left cardiac ventricle of nude mice and then subcutaneously injected 15d-PGJ2 for 6 weeks. The histomorphometrical analysis, including bone volume and microstructure, revealed that 15d-PGJ2 inhibited bone destruction by metastatic breast cancer cells. These results demonstrate that 15d-PGJ2 may inhibit migration/invasion of breast cancer cells, prevent RANKL-mediated osteoclast differentiation/ activity, and suppress breast cancer cells-mediated osteolytic lesion in mice. Thus, 15d-PGJ2 can be a therapeutic agent for cancer metastasis to bone.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2571. doi:1538-7445.AM2012-2571
Abstract 2573: Carnosol and carnosic acid, from rosemary, promote endoplasmic reticulum stress and androgen receptor degradation in prostate cancer cells
Authors: Petiwala Sakina M. , Li Gongbo , Johnson Jeremy J. 
Published: August 2012

Abstract
Background: Prostate cancer is one of the most prevalent forms of cancer among men, especially in the United States. Previously, we have shown that carnosol, a dietary diterpene from rosemary (Rosmarinus officinalis), has a unique function in that it is a dual disruptor of androgen and estrogen receptor alpha. Herein, we examined how carnosol and another dietary diterpene from rosemary, carnosic acid, promote endoplasmic reticulum (ER) stress and modulate the activity and expression of androgen receptor (AR). Materials and Methods: Experiments were performed using the prostate cancer cell lines 22Rv1 and LNCaP cells. Cell proliferation and cell viability were studied using BrdU and MTT assay respectively. Western blotting, ELISA and siRNA were used to evaluate the relationship between ER stress and androgen receptor degradation. Results: Both, carnosic acid and carnosol, inhibited growth and decreased the cell viability of 22Rv1 and LNCaP cells in a dose-dependent manner. The anti-proliferative effect was associated with apoptosis as evidenced by a significant increase in levels of cleaved caspase-3 protein. Interestingly, these diterpenes modulated proteins associated with ER stress including BiP, IRE1 and CHOP. Furthermore, we saw a dose-dependent decrease in expression of AR in 22Rv1 and LNCaP cells when treated with either carnosol or carnosic acid. The proteasome has been shown to be regulated by multiple proteins including proteins associated with ER stress. The AR expression increased in presence of proteasome inhibitor, MG-132, suggesting that decrease in AR expression was due to proteasomal degradation. Carnosic acid and carnosol, also showed a decrease in expression of prostate-specific antigen (PSA) levels in a dose-dependent manner. Conclusion: Both, carnosic acid and carnosol, induce ER stress-mediated apoptotic cell death in prostate cancer cell lines, 22Rv1and LNCaP cells, leading to disruption of AR expression. Our data suggests that these natural diterpenes possess strong anticancer activity and should be evaluated further as potential chemopreventive and/or chemotherapeutic agents for controlling prostate cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2573. doi:1538-7445.AM2012-2573
Abstract 2575: DNA microarray and connectivity map analysis reveals estrogen-like activity of Chinese medicinal formula Si-Wu-Tang
Authors: Liu Mandy M. , Wen Zhining , Wang Zhijun , Zuo Zhong , Chow Moses S.S. , Shi Leming , Huang Ying 
Published: August 2012

Abstract
To pursue a systematic approach for discovery of potential mechanisms of action and new therapeutic use of traditional herbal medicines, we used DNA microarray, bioinformatics and the “Connectivity Map” (CMAP) analysis to investigate the gene expression profiling of Chinese herbal medicines. We demonstrated that this approach can be used to elucidate novel molecular mechanisms for the Chinese medicinal formula Si-Wu-Tang (SWT) which is widely used for women's health in Asian countries. The human breast cancer MCF-7 cells treated with beta-estradiol (E2, 0.1 µM) or SWT extract (0.0256, 0.256, and 2.56 mg/ml) for six hours showed significant gene expression changes. The differentially expressed genes related to SWT treatment were used to compare with the gene expression profiles of 1,309 compounds in the CMAP database. Such comparison revealed that the CMAP profile of E2-treated MCF-7 cells showed an excellent match with SWT treatment (permutation p&lt;0.00001), consistent with SWT's widely claimed use for women's diseases and suggesting a phytoestrogen effect. Many genes strongly up-regulated by E2 were similarly upregulated by SWT, e.g., GREB1, a well-known estrogen regulated gene. Of interest with regard to the potential cancer preventive activity of SWT, the oncogenes MYBL1 and cyclin D1 were found to be strongly induced by E2 but not by SWT. In addition, SWT inhibited expression of estrogen receptor (ER)-alpha, but not ER-beta. Consistently, at low concentration (1.5 and 3.0 mg/ml), SWT stimulated MCF-7 (ER-positive) cell growth, while at high concentration (&gt; 6.0 mg/ml), it inhibited the growth of MCF-7. The combination of SWT with tamoxifen, a selective estrogen receptor modulator, demonstrated enhanced growth inhibitory effects on MCF-7 cells. The results our study suggest that SWT may possess a non-toxic chemopreventive effect for human breast cancer. This study also demonstrated the feasibility of using microarray gene expression profiling in combination with the CMAP data mining to discover new molecular signature that are present in natural products.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2575. doi:1538-7445.AM2012-2575
Abstract 2577: Blocking Janus activated kinase-2 activation by DIM suppresses ovarian tumor growth in vitro and in vivo
Authors: Kandala Prabodh K. , Srivastava Sanjay K. 
Published: August 2012

Abstract
Ovarian cancer is one of the leading causes of gynecological deaths in the United States and several other countries. Genetic alterations including overexpression of EGFR and STAT-3 play a crucial role in the signal transduction pathways that regulate key cellular functions such as cell survival, proliferation, metastases etc. Several epidemiological studies suggested a decreased risk of ovarian cancer in the population consuming Brassica vegetables. 3,3′-diindolylmethane (DIM) is an indole compound present in Brassica vegetables. In our previous studies, we have demonstrated that DIM induces apoptosis in ovarian cancer cells by inhibiting the activation STAT-3. However, the exact mechanism of STAT-3 regulation by DIM was not clear. Accumulating evidences suggest that Janus Activated Kinases (JAK's) play a crucial role in regulating STAT-3. Our current results show that DIM inhibits the activation of JAK-2 by blocking its phosphorylation at Tyr-1007/1008 in a concentration-dependent manner in SKOV-3 and OVCAR-3 cells. Inhibition of JAK-2 phosphorylation by DIM was as early as one hour after DIM treatment. The expression of survivin was significantly reduced by DIM. IL-3 is a cytokine that specifically activates JAK-2. Treatment of SKOV-3 or OVCAR-3 cells with 10ng/ml IL-3 for 15min not only increased the activation of JAK-2 and STAT-3, but also induced the expression of STAT-3. DIM treatment almost completely blocked IL-3 induced phosphorylation of JAK-2 and STAT-3 in SKOV-3 and OVCAR-3 cells. Several studies have shown that JAK's are regulated by EGFR, hence to test this, cells were stimulated with EGF, a specific ligand of EGFR. As expected, EGF treatment increased the activation of JAK-2 and STAT-3 in SKOV-3 cells. Nonetheless, DIM treatment blocked the phosphorylation of JAK-2 and STAT-3 induced by EGF. Furthermore, our in vivo studies demonstrated that oral administration of 3 mg DIM for 40 days significantly suppressed the growth of ovarian tumors xenografts in athymic nude mice. The tumors of DIM treated mice exhibited reduced phosphorylation of JAK-2, EGFR and STAT-3 and increased apoptosis. These results indicate that DIM induces apoptosis in ovarian tumor cells by regulating JAK-2 activation in vitro and in vivo. [Supported in part by R01 grants CA 106953 and CA 129038 awarded to S.K.S by National Cancer Institute, NIH]
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2577. doi:1538-7445.AM2012-2577
Abstract 2578: Anticancer action of garcinol in vitro and in vivo is mediated through inhibition of STAT-3 signaling
Authors: Ahmad Aamir , Aboukameel Amro , Ali Shadan , Li Yiwei , Bao Bin , Kong Dejuan , Banerjee Sanjeev , Sarkar Fazlul H. 
Published: August 2012

Abstract
Garcinol, obtained from Garcinia indica, has exhibited some promising anticancer activity. In particular, our earlier work has demonstrated its ability to inhibit cell proliferation, and induce apoptosis in multiple cancer cell lines originated from breast, prostate as well as pancreatic cancer. However, its exact mechanism of action remains largely unclear. Here we show that garcinol targets signal transducer and activator of transcription-3 (STAT-3) signaling pathway. STAT-3 is frequently found to be activated in many cancer types and this is the first report on such action of garcinol leading to its anticancer effects. Garcinol inhibited total as well as phosphorylated STAT-3 in breast, prostate and pancreatic cancer cell lines, and was also found to inhibit cell migration and colony formation of all the cancer cell lines tested. STAT-3 phosphorylation was inhibited by garcinol in a dose-dependent manner. We also observed an inhibitory effect of garcinol on IL-6-induced STAT-3 phosphorylation and production of uPA and VEGF which might explain the reduced migration and aggressiveness in cells treated with garcinol. The results were further verified in vivo in a MDA-MB-231 breast cancer mouse xenograft model where administration of garcinol significantly inhibited tumor growth, and western blot analysis of tumor lysates indicated reduced STAT-3 expression and activation. These results indicate that garcinol may have translational potential as chemopreventive or therapeutic agent against multiple cancers through inhibition of STAT-3 signaling pathway.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2578. doi:1538-7445.AM2012-2578
Abstract 2579: Capsaicin inhibits β-catenin signaling in pancreatic cancer cells by disrupting nuclear β-catenin/TCF-1 complex: critical role of STAT-3
Authors: Pramanik Kartick C. , Boreddy Srinivas Reddy , Srivastava Sanjay K. 
Published: August 2012

Abstract
β-catenin/TCF signaling plays an important role in normal development. However, its aberrant activation is associated with several cancers including pancreatic cancer. In our previous study, we have shown that capsaicin-induced apoptosis in pancreatic cancer cells was associated with mitochondrial depolarization and oxidative stress. In the present study, we evaluated the effect of capsaicin on β-catenin/TCF signaling. In a concentration and time-dependent study, we observed that capsaicin treatment inhibits the activation of disheveled (Dsh) and phosphorylation of STAT-3 at Tyr705 in L3.6PL, Panc-1 and MiaPaCa-2 pancreatic cancer cells. Capsaicin treatment activated GSK-3β by inhibiting its phosphorylation and further activated APC and Axin multicomplex leading to the ubiquitination and degradation of β-catenin. Pre-treatment of cells with MG-132 blocked capsaicin-mediated proteasomal degradation of β-catenin. The expression of TCF-1 and β-catenin-responsive proteins c-myc and cyclin D1, were also decreased in response to capsaicin treatment. Significant cleavage of caspase-9, caspase-3 and PARP was observed in all the cell lines. To establish the involvement of β-catenin in capsaicin-induced apoptosis, cells were treated with LiCl or SB415286, inhibitors of GSK-3β. Our results reveal that capsaicin treatment suppressed LiCl-mediated activation of β-catenin signaling. Our results further showed that capsaicin blocked the nuclear translocation of β-catenin and TCF-1. The immunoprecipitation results also indicated that capsaicin treatment reduced the interaction of β-catenin with TCF-1 in the nucleus. Interestingly, STAT-3 over expression or STAT-3 activation by IL-6, significantly increased the levels of β-catenin and attenuated the effects of capsaicin in inhibiting β-catenin signaling. These observations indicate the direct regulation of β-catenin by STAT-3 in our model. Taken together, our results suggest that capsaicin-induced apoptosis in pancreatic cancer cells was associated with the inhibition of β-catenin signaling due to the dissociation of β-catenin/TCF-1 complex leading to apoptosis, and this process was orchestrated by STAT-3. [Supported in part by R01 grants CA106953 and CA129038 (to S.K.S) awarded by the National Cancer Institute].
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2579. doi:1538-7445.AM2012-2579
Abstract 2580: Induction of estrogen receptor alpha by GW9662 sensitizes mammary glands to tamoxifen treatment in organ culture
Authors: Mehta Rajendra G. , Peng Xinjian , Roy Sarbani , Mehta Rajeshwari , Kopelovich Levy 
Published: August 2012

Abstract
Peroxisome proliferator-activated receptor gamma (PPARδ) are ligand activated nuclear receptor and binds to natural and synthetic ligands. Earlier we had reported that PPARδ agonist troglitazone inhibited the development of precancerous lesions induced by DMBA in mouse mammary gland organ culture (MMOC). In the present study we evaluated the effects of PPARδ agonist GW7845 and antagonist GW9662 on the development of 7,12 dimethylbenz(a)anthracene (DMBA)-induced mammary alveolar lesions (MAL) in ER negative mammary glands in MMOC. The results showed that both GW7845 and GW9662 inhibited development of ER- MAL in MMOC. Since PPARδ and ER cross talk has been reported in the literature, we determined the effects of GW9662 on the induction of ER and PR in this model. Real-time PCR studies and immunohistochemical analyses showed that GW9662 induced ERα in the absence of estradiol, whereas GW7845 did not induce ERα under these conditions. Both GW7845 and GW9662 failed to suppress mRNA expression of PPARδ in the mammary glands that are otherwise ER negative. However GW9662 suppressed the expression of PPARδ response genes adipsin and aP2. Conversely, GW7845 an agonist of PPARδ enhanced the expression of aP2 and adipsin. These results suggested that the effects of these agents are mediated by PPARδ in MMOC. Finally, Tamoxifen does not inhibit MAL in MMOC, however sequential treatments with GW9662 followed by Tamoxifen suppressed development of DMBA-induced MAL in these glands. Since the ER negative breast cancer patients are generally not treated with SERM, inducing ERα in the mammary cells by GW9662 possibly could make them responsive to Tamoxifen or other SERM. [This work was supported by N01 CN433303]
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2580. doi:1538-7445.AM2012-2580
Abstract 2582: 2-ME2-induced biological effects in prostate cancer: Role for miR127-3p/SET8
Authors: Xie Jianping , Batth Izhar Singh , Bedolla Roble , Li Guiming , Chen Hung-I Harry , Chen Yidong , Ghosh Rita , Kumar Addanki Pratap 
Published: August 2012

Abstract
Prostate cancer is the second most common cause of death related to cancer in Western societies. 2-Methoxyestradiol (2-ME2), an endogenous metabolite of 17-α estradiol inhibits tumor cell proliferation in various cancer cells, including the prostate. Previous studies from our laboratory showed that 2-ME2 (i) inhibits proliferation of both androgen responsive and independent cells through induction of apoptosis involving G2/M check point block; (ii) prevents the development of prostate tumors in transgenic adenocarcinoma of mouse prostate (TRAMP) model. Although various molecular targets have been proposed, the mechanism of action behind its antiproliferative activity is still uncertain. Here we investigated the possible role for 2-ME2 induced antiproliferative activity by examining the altered regulation of microRNA (miRNAs). MicroRNA expression profiling identified miR127-3p as most significantly up regulated in response to 2-ME2 treatment in androgen independent (PC-3) cells. We have also identified histone methylase SET8 as a potential target of miR 127-3p. We have validated these data using Q-PCR. Further 2-ME2 treatment reduced binding of multiple transcription factors including Sp1, Sp3 and NFκB to the FLIP promoter as evidenced by transient expression assays, ChIP and gel-shift assays. Our findings indicate that 2-ME2 suppresses proliferation and induces apoptosis in prostate cancer cells possibly through miR127-3p/SET8 mediated regulation of FLIP. Supported by NIH CA 135451 (APK).
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2582. doi:1538-7445.AM2012-2582
Abstract 2586: Pomegranate components modulate distinct pathways in prostate cancer cells
Authors: Munagala Radha , Aqil Farrukh , Gupta Ramesh C. , Higashi Richard M. , Vadhanam Manicka V. 
Published: August 2012

Abstract
Pomegranate juice, when provided as whole juice, modulates specific pathways in prostate cancer cells that are not reflected when its major constituents were tested independently. In order to identify these bioactive components of pomegranate, the peel (P) and arils (J) were isolated, juiced separately and extracted with 80% methanol (PE and JE). The components were enriched using a SPE C18 cartridge and, eluted as fraction I (P-I and J-I - contains mostly polar compounds) and fraction II (P-II and J-II - contains mostly non-polar compounds). Analysis by HPLC-PDA and by direct infusion analysis of these fractions by FTICR-MS revealed the J-I consisted of mostly phenolics including the three anthocyanins in its mono- and di-glycoside forms. P-I consisted mostly of punicalin and, the punicalagins A and B, while P-II and J-II consisted mostly of ellagitannins and free ellagic acid. The ORAC values as Trolox equivalent for the various fractions at 10 µg/ml were: Total peel extract (PE) - 1.64 compared with 2.74 for P-I and 4.01 for P-II, while for the total juice extract (JE) it was 2.62 compared with 7.01 for J-I and 5.47 for J-II. To identify the molecular mechanisms, the individual fractions of peel and juice were tested in prostate cancer cell lines, LNCaP and PC3 and analyzed by Cancer/Apoptosis Phospho Antibody Array and western blot analysis. In LNCaP cell line, BCL-2, PTEN, Cdc25A, p53 and STAT6 were hyper-phosphorylated by J-II, while they were unaltered by J-I. Similarly, GSK3 alpha and beta were hyper-phosphorylated by J-I and unmodified by J-II. When peel fractions were tested, Cdc25C, BCL-2, CREB and JAK were hypo-phosphorylated by P-II, whereas they were unaltered by P-I. Other molecules, such as IRS-1, MAP Kinase, PTEN, STAT3 and JAK2 were hypo-phosphorylated by P-II, and were hyper-phosphorylated by P-I. In PC3 cell line, BCL-2, p53 and CREB were hypo-phosphorylated by J-II, while they were unaltered by J-I. However, PTEN and p70 were hypo-phosphorylated by J-II and hyper-phosphorylated by J-I, while, CDK2, STATs 1, 3 and 6 were hypo-phosphorylated by P-II, they were unaltered by P-I fraction. Thus the components of peel and juice fractions demonstrate unique properties and the ability to modulate distinct pathways in androgen-dependent and independent prostate cancer cells providing a rich set of potential therapy or adjuvant applications. This work is supported by NCI grant CA143676.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2586. doi:1538-7445.AM2012-2586