bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3658: Sulforaphane suppresses 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced mouse epidermal JB6 P+ cell transformation through epigenetic re-activation of Nrf2.
Authors: Su Zheng-Yuan , Shu Limin , Zhang Chengyue , Khor Tin Oo , Lee Jong Hun , Wu Tien-Yuan , Conney Allan H. , Kong Ah-Ng Tony 
Published: August 2014

Abstract
Sulforaphane (SFN), an isothiocyanate in cruciferous vegetables including broccoli, cabbage, cauliflower, Chinese cabbage, and watercress, has strong anti-cancer/cancer chemopreventive potentials. Transcription factor nuclear factor erythroid 2 p45 (NF-E2)-related factor 2 (Nrf2) plays an important role in regulating the expressions of cellular antioxidant and detoxification enzymes. In this study, we investigated the preventive effect of SFN on tumor promoter-induced transformation in mouse skin epidermal JB6 promotion-sensitive (JB6 P+) cells, which might be involved with the activation of Nrf2. After 5 days pre-treatment, the results showed that SFN significantly inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced neoplastic transformation. SFN enhanced nuclear translocation of Nrf2 and increased the Nrf2 downstream target enzymes including HO-1, NQO1, and UGT1A1 at both the transcriptional and protein levels. Comparing to shMock-transfected cells, TPA effectively induced colony formation in shNrf2 knockdown transfected cells were more resistant to the inhibitory effects of SFN. SFN's induction of Nrf2, HO1, and NQO1 protein expressions in shNrf2-transfected cells were lower than those in shMock-transfected cells. Epigenetics study showed that SFN suppresses methyltion ratio of the first fifteen CpGs in the promoter of Nrf2 gene in JB6 P+ cells utilizing bisulfite sequencing. Furthermore, SFN strongly reduced the protein expressions of DNA methyl transferases (DNMTs) including DNMT1, DNMT3a, and DNMT3b. In terms of histone deacetylases (HDACs), SFN not only inhibited total HDAC activity but also decreased the protein levels of HDAC1, HDAC2, HDAC3, and HDAC4, significantly. Taken together, these findings suggest that epigenetic re-activation of Nrf2 with subsequent induction of Nrf2 downstream target genes by SFN may provide insights into the chemopreventive mechanism of SFN against tumor promoter-induced mouse skin carcinogenesis.
Citation Format: Zheng-Yuan Su, Limin Shu, Chengyue Zhang, Tin Oo Khor, Jong Hun Lee, Tien-Yuan Wu, Allan H. Conney, Ah-Ng Tony Kong. Sulforaphane suppresses 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced mouse epidermal JB6 P+ cell transformation through epigenetic re-activation of Nrf2. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3658. doi:10.1158/1538-7445.AM2013-3658
Abstract 3660: Apigenin suppresses IKK activation and downstream signaling leading to prostate cancer inhibition.
Authors: Shukla Sanjeev , Datt Manish , Chance Mark R. , Gupta Sanjay 
Published: August 2014

Abstract
Inhibitor of Nuclear Factor-κB kinase (IKK) complex is the master regulator of the NF-κB signaling pathway. IKK complex activation contributes to major cellular processes and plays a key role in the pathogenesis various human malignancies including prostate cancer. Recently, catalytic IKKs represent attractive targets for intervention with small molecule kinase inhibitors. We aimed to develop apigenin, a plant flavone, as a potent inhibitor of the IKK-kinase domain. IKK complex consist of structurally similar IKKα and IKKβ kinases. Both contains a kinase domain, a leucine-zipper motif through which the catalytic subunits dimerize, and a helix-loop-helix domain followed by a C-terminal tail that, when unphosphorylated interacts with IKKγ, the non-catalytic subunit. Screening of human prostate tumors demonstrated an increase in IKKα in low and high Gleason grade, whereas, IKKβ was higher in benign and low grade tumors. Phosphorylation of IKKα (Ser176/180) and IKKβ (Ser177/181) was significantly increased in prostate tumors compared to benign tissues. Treatment of human prostate cancer 22Rv1 and PC-3 cells to apigenin resulted in a decreased phosphorylation of IKKα/β in dose-dependent fashion, which correlated with lower proliferation and invasiveness. Ex Vivo IKK complex pull down assay using sepharose beads also confirmed direct binding of apigenin with IKK complex. In vivo studies with PC-3 and 22Rv1 xenografts in athymic nude mice further demonstrated that oral intake of apigenin at doses of 20 and 50μg/mouse/day over an 8-wk period resulted in a marked reduction in tumor growth, IKK activity, IKK phosphorylation, and NF-κB/p65 at both doses of apigenin. Furthermore, 3D structural in silico modeling analysis with PS1145, a known IKK inhibitor and apigenin were assessed for IKKα and IKKβ separately for protein-ligand docking studies using glide score. Apigenin was well anchored by hydrogen bonds with amino acid resides in the IKK complex protein at both ends. All three hydroxyl groups of apigenin were favorably oriented around different hydrogen bond acceptor atoms in the protein. Glide score generated by apigenin and PS1145 docking to IKK-α were -8.40 and -5.79, whereas IKK-β were -11.07 and -9.11; lower glide score represents better binding to IKK complex pocket. These results suggest that inhibition of cell proliferation and decrease in tumor growth by apigenin are mediated, at least in part, by its ability to suppress IKK complex and NF-κB signaling pathways.
Citation Format: Sanjeev Shukla, Manish Datt, Mark R. Chance, Sanjay Gupta. Apigenin suppresses IKK activation and downstream signaling leading to prostate cancer inhibition. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3660. doi:10.1158/1538-7445.AM2013-3660
Abstract 3667: Pro-oxidant effects of the green tea catechin, (-)-epigallocatechin-3-gallate in oral cancer cells: A role for the mitochondria.
Authors: Tao Ling , Forester Sarah C. , Lambert Joshua D. 
Published: August 2014

Abstract
(-)-Epigallocatechin-3-gallate (EGCG) is the most abundant polyphenol in green tea (Camellia sinensis). Many laboratory studies have demonstrated its potential cancer chemopreventive effects. Previously, we found that EGCG inhibited cell growth and induced apoptosis in oral squamous carcinoma cells (SCC-25 and SCC-9), and that, EGCG-induced intracellular ROS played a key role in the inhibitory effects. EGCG treatment also caused a significant loss of mitochondrial membrane potential after 72 h, suggesting that mitochondrial dysfunction may have caused the increased intracellular ROS. In the present study, we further explored the role of the mitochondria in EGCG-mediated oxidative stress. We found that EGCG-induced intracellular ROS initially co-localized with the mitochondria of SCC-25 cells (by 1 h) and then spread throughout the cell. Treatment with 100 μM EGCG for 24 h inhibited the activity of mitochondrial membrane complex I by 50% and tended to inhibit complex III. These results demonstrate that EGCG can induce mitochondrial dysfunction in part by impairing electron transfer chain, resulting in increased intracellular ROS. Using qPCR, we found time-dependent changes in several genes. The expressions of thyroid peroxidase (TPO, 2.9-fold), Bcl2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3, 2.2-fold) and glutathione peroxidase 2 (GPX2, 1.2-fold) were increased within 6 h treatment. The latter two genes are related to mitochondrial dysfunction and oxidative stress, respectively. By contrast to cancer cells, EGCG did not induce significant cell growth inhibition and apoptosis in normal human gingival fibroblast cells (HGF-1). EGCG treatment actually reduced intracellular ROS in HGF-1 cells in contrast to the increase observed in the cancer cell lines, indicating selective pro-oxidant effects of EGCG in oral cancer cells. In conclusion, induction of mitochondrial dysfunction and resultant production of intracellular ROS appear to play a significant role in the inhibitory effects of EGCG against oral cancer cells. The differential responses of cancer cells and normal cells to EGCG are being further studied.
Citation Format: Ling Tao, Sarah C. Forester, Joshua D. Lambert. Pro-oxidant effects of the green tea catechin, (-)-epigallocatechin-3-gallate in oral cancer cells: A role for the mitochondria. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3667. doi:10.1158/1538-7445.AM2013-3667
Abstract 3669: Chemoprevention of mammary and prostate cancer by phenethyl isothiocyanate in vivo is associated with suppression of vimentin protein expression.
Authors: Sakao Kozue , Hahm Eun-Ryeong , Singh Shivendra V. 
Published: August 2014

Abstract
Phenethyl isothiocyanate (PEITC), a constituent of many edible cruciferous vegetables (eg, watercress), exhibits in vivo preventive efficacy against cancer in rodents induced by structurally diverse chemical carcinogens. We have also shown recently that dietary administration of PEITC (3 μmol PEITC/g diet) confers significant protection against breast and prostate cancer development in MMTV-neu and TRAMP model, respectively. Prevention of prostate cancer by PEITC administration in TRAMP mice was associated with induction of E-cadherin protein expression. Because suppression of E-cadherin protein level concomitant with induction of mesenchymal markers (eg, vimentin) is a biochemical hallmark of epithelial-mesenchymal transition, a process implicated in cancer metastasis, we hypothesized that PEITC treatment was likely to suppress vimentin protein expression. Contrary to this prediction, exposure of cultured human breast (MDA-MB-231) and prostate cancer cells (PC-3 and DU145) to PEITC resulted in a dose-dependent increase in vimentin protein level, which was observed as early as 6 hours post-treatment and persisted for the duration of the experiment (24 hours). RNA interference of vimentin resulted in a modest augmentation of PEITC-mediated inhibition of MDA-MB-231 and PC-3 cell migration as well as cell viability. Furthermore, the PEITC-induced apoptosis was moderately increased upon siRNA knockdown of vimentin protein level in MDA-MB-231 and PC-3 cells. To our surprise, PEITC administration caused a marked decrease in vimentin protein expression in vivo in tumors of MMTV-neu (breast) and TRAMP mice (prostate). The results of the present study indicate that cancer chemoprevention by PEITC in vivo is associated with suppression of vimentin protein expression. The present study was supported by the grant CA101753-09 awarded by the National Cancer Institute.
Citation Format: Kozue Sakao, Eun-Ryeong Hahm, Shivendra V. Singh. Chemoprevention of mammary and prostate cancer by phenethyl isothiocyanate in vivo is associated with suppression of vimentin protein expression. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3669. doi:10.1158/1538-7445.AM2013-3669
Abstract 3701: Tomato carotenoids and testosterone modulate mRNA and miRNA profiles during prostate carcinogenesis.
Authors: Thomas-Ahner Jennifer M. , Wan Lei , Tan Hsueh-Li , Moran Nancy E. , Elsen Amy C. , Pearl Dennis K. , Erdman John W. , Clinton Steven K. 
Published: August 2014

Abstract
There is considerable evidence supporting the hypothesis that tomato carotenoids may contribute to prostate cancer prevention however the mechanisms remain uncertain. We propose that bioactive tomato components, such as lycopene, may impact testosterone signaling to inhibit prostate carcinogenesis. Four week-old C57/BL6 WT and TRAMP male mice were fed either control (AIN93G), 10% tomato powder or 0.25% lycopene beadlets. At eight weeks of age, mice were randomized among treatments: intact, castration, or castration + 2.5mg/kg testosterone repletion and animals sacrificed at 10 weeks of age. Prostate gene expression was quantified by Nanostring nCounter was used to quantify prostate gene expression with a 200 gene murine prostate carcinogenesis custom codeset and miRNA with codeset v1.1. Carotenoid analysis is by HPLC and proliferation (Ki67) by immunohistochemical evaluation. Feeding dietary tomato or lycopene increased serum lycopene, for example, in WT mice concentrations reached 335 +/- 33 nmol/L and 337 +/- 34 nmol/L in tomato and lycopene fed animals, respectively. As expected, the TRAMP genotype and testosterone stimulate proliferation with diet as a modulating factor. In the WT intact prostate, the tomato powder and lycopene diet decreased proliferation (p&lt;0.009). The TRAMP genotype and endocrine status impacted the expression of multiple genes and miRNAs in several distinct patterns. For example, Birc5, Ki67, PCNA, BRCA1, ATM, Aurora kinase A / B, Cdc25c, Cyclin B2, cyclin E2, Fox M1,and miRs 15b, 16, 25, 200a, 200b, and 429 are increased in the TRAMP prostate, only when testosterone is present. Alternatively, TMPRSS2, CD31, CD34, Cox 2, nCad, Cyclin D1, Keratin 5, Shh, and p63, and miRs 145, 205, 328, and 423-5p are decreased in the TRAMP prostate in the presence of testosterone. Nkx3.1, miR 148a, and miR 375 are decreased upon castration whereas beta catenin, FGFR1 and TNF alpha are increased. Tomato and / or Lycopene modestly decreased expression of eCad, HIF 1 alpha, Paxillin, RxR alpha, Sca 1 and Vimentin and increased expression of CD133 and miR 22. These highly controlled in vivo studies document the strong interactions between genetic defects in the prostate, the hormonal environment, and diet in modulating early prostate carcinogenesis.
Citation Format: Jennifer M. Thomas-Ahner, Lei Wan, Hsueh-Li Tan, Nancy E. Moran, Amy C. Elsen, Dennis K. Pearl, John W. Erdman, Steven K. Clinton. Tomato carotenoids and testosterone modulate mRNA and miRNA profiles during prostate carcinogenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3701. doi:10.1158/1538-7445.AM2013-3701
Abstract 3712: p21-activated kinase-1 in the prevention of inflammation-driven colon cancer.
Authors: Khare Vineeta , Dammann Kyle , Jambrich Manuela , Roig Andres , Shay Jerry , Gasche Christoph 
Published: August 2014

Abstract
Chronic gut inflammation in inflammatory bowel diseases (IBD) predisposes to the development of colorectal cancer, causing increased mortality. Use of mesalamine in the treatment and remittance of ulcerative colitis (UC) modulates the risk of neoplastic progression. We have previously reported (Khare V, et al. Biochem Pharm 2012) that p-21 activated kinase-1 (PAK1) mediates mesalamine activity by orchestrating MAPK signaling; Wnt-β catenin pathway and cell adhesion; all implicated in the colon carcinogenesis. Since mesalamine has primarily an anti-inflammatory function, we evaluated the role of PAK1, its target, in IBD and in colitis-associated cancer (CAC). PAK1 expression was scored by immunohistochemistry in human samples from IBD, CAC and normal mucosa. Compared to normal mucosa and Crohn's disease, a higher PAK1 expression was detected in UC which further increased in CAC. PAK1 expression was also elevated in the inflamed mucosa and carcinomas in IL-10−/− mouse model of colitis. The efficacy of mesalamine in reducing inflammation and tumor incidence in these mice has been previously reported (Brown JB et al, Gastroenetrology 2010). The consequence of PAK1 overexpression was further investigated in vitro. Normal diploid colon epithelial cells (HCEC-1CT) showed higher proliferation (46 ± 3.1% increase) upon overexpression of wildtype (wt) PAK1 while dominant negative (dn) PAK1 overexpression reduced proliferation (25% ± 2.5 decrease) compared to control. Apoptosis (Annexin V staining) was reduced in HCEC-1CT overexpressing wtPAK1 (1.2% ± 0.40) compared to dnPAK1 (11.6% ± 0.3) and control (16% ± 0.83). Mesalamine treatment (20mM) was effective in counteracting the effect of PAK1 overexpression by reducing cell proliferation and inducing apoptosis. Treatment of cells with specific inhibitors (PD98059/LY294002/Rapamycin) of signaling pathways (MEK/PI3K/mTOR) demonstrated that mesalamine regulated PAK1 expression by the MEK, PI3K and mTOR signaling pathways. Our data indicate that (1) PAK1 is upregulated in UC and in CAC, (2) PAK1 may be utilized as a predictive marker for the development of CAC, and (3) PAK1 is a viable target for chemoprevention in the setting of colitis. Mesalamine counteracts PAK1 expression and its effect on cell proliferation and apoptosis. In the longterm management of UC mesalamine may protect from CAC through inhibition of PAK1.
Citation Format: Vineeta Khare, Kyle Dammann, Manuela Jambrich, Andres Roig, Jerry Shay, Christoph Gasche. p21-activated kinase-1 in the prevention of inflammation-driven colon cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3712. doi:10.1158/1538-7445.AM2013-3712
Abstract 3719: xCT inhibition suppresses CD44v-positive stem-like tumor cells, which are resistant to EGFR-targeted therapy in head and neck squamous cell carcinoma.
Authors: Yoshitake Momoko , Nagano Osamu , Nakagawa Taneaki , Saya Hideyuki 
Published: August 2014

Abstract
Given that cancer cells are exposed to environmental stressors such as oxygen or nutrient deficiency, low pH, inflammatory mediators, and ROS during tumor progression,the ability to avoid the consequences of such exposure is required for cancer cell survival. CD44 is a major marker for stem-like cancer cells in many epithelial tumors and has been implicated in tumor growth, invasion, and metastasis. CD44 exists in numerous variant isoforms (CD44v) that are generated through alternative mRNA splicing. We recently showed that interaction of CD44v with the cystine transporter subunit xCT stabilizes the latter protein and thereby potentiates the ability of cancer cells to defend themselves against reactive oxygen species (ROS). Stem-like cancer cells in which defense against ROS is enhanced by CD44v are thus thought to drive tumor growth, chemoresistance and metastasis.
In the present study, we show that head and neck squamous cell carcinoma (HNSCC) cells that express CD44v rely on the activity of the cystine transporter subunit xCT for control of their redox status. Ablation of CD44v attenuated the xCT dependency as well as tumor-forming ability in HNSCC cells, and xCT inhibition selectively induced apoptosis in CD44v-expressing tumor cells. In contrast, CD44v-negative differentiated cells manifest epidermal growth factor receptor (EGFR) activation and rely largely on EGFR activity for their survival. Combined treatment with inhibitors of xCT-dependent cystine transport and of EGFR may induce apoptosis in distinct subpopulations of HNSCC tumor cells.
Citation Format: Momoko Yoshitake, Osamu Nagano, Taneaki Nakagawa, Hideyuki Saya. xCT inhibition suppresses CD44v-positive stem-like tumor cells, which are resistant to EGFR-targeted therapy in head and neck squamous cell carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3719. doi:10.1158/1538-7445.AM2013-3719
Abstract 3722: HH/GLI signaling as a new therapeutic target governs the stemness of head and neck cancer stem cells.
Authors: Yan Ming 
Published: August 2014

Abstract
Patients with advanced head and neck squamous cell carcinoma (HNSCC) show poor prognosis to current therapy and tumor recurrence and metastasis are frequently observed. The discovery of cancer stem cell (CSC) markers is crucial for developing novel therapeutic strategies by targeting these CSCs. To address this issue, we used sphere culture method to enrich CSCs from their isogeneic adherent cultured HNSCC cells. Compared with adherent cultured HNSCC cells, the microspheres of HNSCC cells were more clonogenic in nude mice, and expressed higher levels of shh and Gli-2, and Gli-2 translocated into the nuclear of the spheres, which showed that hedgehog signal pathway was activated in the cancer stem cells like subpopulations of HNSCC. Further study found that Gli-2, one of the main transcriptional activators of HH/GLI signal, was expressed in 60 (44%) of the 136 HNSCC samples and the expression was significantly associated with poor clinical outcomes. Only 44% of the patients whose tumors expressed Gli-2 survived at 5 years after surgery compared to 77% of those whose tumors lacked the Gli-2 expression (P &lt; 0.0001). Both cyclopamine and GANT61 effectively inhibited Gli expression, slowed cell growth, promoted G1 arrest, increased apoptosis and inhibited migration of HNSCC cells. Together with the findings, we conclude that activation of HH/GLI pathway plays an important role in maintaining the stemness of HNSCC, and strongly associates with HNSCC progression, suggesting that a subset of OSCC patients may benefit from anti-HH/GLI therapies.
Citation Format: Ming Yan. HH/GLI signaling as a new therapeutic target governs the stemness of head and neck cancer stem cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3722. doi:10.1158/1538-7445.AM2013-3722