bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1890: PLEK2 contributes to lung cancer progression through upregulation of NDRG1 expression
Authors: Hsieh Yi-Pin , Liu Hui-Chia , Huang Hao-Yu , Tang Wan-Jiun , Lee Tai-Lin , Tsai Meng-Feng 
Published: July 2017

Abstract
PLEK2 is one of the pleckstrin homology domain (PH domain) proteins. Recently studies suggested that PLEK2 may play a critical role in T lymphocyte migration through by PI3K/AKT dependent and independent pathways. However, the biological functions of PLEK2 in lung cancer is not clear. We detected the expression of PLEK2 in various lung adenocarcinoma cell lines using quantitative RT-PCR methods. The results indicated that PLEK2 expression significantly positive correction with cancer cell migration and invasion ability. Forced expression of PLEK2 in lung cancer cells exhibited markedly promoting in the proliferation rate, anchorage independent growth, cell motility and invasion, whereas knockdown of PLEK2 was found to suppress lung cancer cell progression. In addition, we also reported that PLEK2 expression induce lung cancer cell epithelial-mesenchymal transition (EMT) phenomenon, and involve in chemotherapeutic drug resistance through upregulation NDRG1 gene expression. Overexpression of NDRG1 in PLEK2-knockdown cell line restored cancer cell proliferation, migration, and invasion. These results will provide information and help us to understand the roles of NDRG1 in lung cancer cells.
Citation Format: Yi-Pin Hsieh, Hui-Chia Liu, Hao-Yu Huang, Wan-Jiun Tang, Tai-Lin Lee, Meng-Feng Tsai. PLEK2 contributes to lung cancer progression through upregulation of NDRG1 expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1890. doi:10.1158/1538-7445.AM2017-1890
Abstract 1893: Alpha-tubulin acetyltransferase, MEC-17, regulates cancer cell morphology and migration through epithelial-mesenchymal transition suppression and cell polarity disruption
Authors: Lee Cheng-Che , Chang Chi-Yen , Lin Chi-Min , Chang Jang-Yang 
Published: July 2017

Abstract
Acetylation of α-tubulin has characterized as a key process for microtubule stabilization, and it can regulate cell spreading and modulate the dynamics of focal adhesion. MEC-17, a newly identified alpha-tubulin-N-acetyltransferase 1, serves as the major α-tubulin acetyltransferase to promote α-tubulin acetylation in vitro and in vivo. However, the physiological function of MEC-17 in cancer cells and its effect on MT acetylation during cell morphogenesis and migration has remained elusive. In the present study, our results showed that overexpression of MEC-17 induced increment of cell focal adhesion area, suppressed pseudopods formation in three-dimension collagen-embedded cultured environment and inhibited cancer cell migratory and invasive abilities. These changes were further proved to be caused by epithelial-mensenchymal transition (EMT) repression, cell polarity disruption caused by alteration of Golgi orientation and cdc42 activity and the decrease in the phosphorylation of extracellular signal regulatedkinase1/2 (Erk1/2). On the contrary, silencing of endogenous MEC-17 by specific shRNA accelerated the pseudopods formation and EMT process, which lead to facilitating the cell migration. Taken together, these results demonstrated that the important role of MEC-17 in the modulation of intrinsic cellular morphogenesis and migratory and invasive functions through regulation of EMT and polarization. (The study was supported by the following grants: MOST 103-2320-B-006-036-MY3 and MOST 105-2325-B-400-001 from the Ministry of Science and Technology of Taiwan, ROC)
Citation Format: Cheng-Che Lee, Chi-Yen Chang, Chi-Min Lin, Jang-Yang Chang. Alpha-tubulin acetyltransferase, MEC-17, regulates cancer cell morphology and migration through epithelial-mesenchymal transition suppression and cell polarity disruption [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1893. doi:10.1158/1538-7445.AM2017-1893
Abstract 190: Identification of compound isolated from Beilschmiedia tsangii as a liver cancer specific NRF2 inhibitor
Authors: Chen Yi Siao , Lai Chih Chung , Kuo Yi Ping , Chang Hsun Shuo , Chen Ih Sheng , Yen Chia-Hung 
Published: July 2017

Abstract
Drug resistance is the main cause of cancer recurrence and a major obstacle to the success of anticancer therapy. NRF2, a pivotal transcription factor regulates antioxidant response and detoxification, has been shown to participate in the development of cancer drug resistance. Functional suppression of NRF2 rendered cancer cell more susceptible to anticancer treatments. Beilschmiedia tsangii Merr. (Lauraceae) is a medium-sized evergreen tree. It has been reported that Beilschmiedia extract showed a strong antioxidant activity. In continuation of our bioactivity studies on this species, we tested the effects of 23 compounds isolated from the B. tsangii on NRF2 activity. We identified rel-(7R,8R,7′R,8′R)-3,4,3′,4′-dimethylene-dioxy-5,5′-dimethoxy-7,7′-epoxylignan (BT04) significantly inhibited NRF2 activity in liver cancer cell (Huh7) with an IC50 value of 17 μM, but not in keratinocyte (HacaT cell). By contrast, luteolin, a known NRF2 inhibitor, suppressed NRF2 activity in both Huh7 cell and HacaT cell. Moreover, the mRNA level of NRF2 target genes, NQO1 and HO1, were significantly decreased in Huh7 upon BT04 treatment, while those NRF2 target genes remained unchanged in BT04-treated HacaT cell. A moderate cytotoxic effect of BT04 on Huh7 cell was also observed. Accordingly, our result suggested that BT04 can specifically inhibit NRF2 activity in liver cancer, which in turn indicated that BT04 could be a potential adjuvant to improve chemoresistance.
Citation Format: Yi Siao Chen, Chih Chung Lai, Yi Ping Kuo, Hsun Shuo Chang, Ih Sheng Chen, Chia-Hung Yen. Identification of compound isolated from Beilschmiedia tsangii as a liver cancer specific NRF2 inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 190. doi:10.1158/1538-7445.AM2017-190
Abstract 1901: DNMT1 is involved in esophageal squamous cell carcinoma (ESCC) and self-renewal ability of ESCC-cancer stem cells
Authors: Teng Ying , Yu Xiying , Yuan Hui , Guo Liping , Jiang Wei , Lu Shih-Hsin 
Published: July 2017

Abstract
DNA methylation mediated by DNA methyltransferase 1 (DNMT1) plays an important role in carcinogenesis and self-renewal ability of cancer stem cells (CSCs). However, the function of DNMT1 in esophageal squamous cell carcinoma (ESCC) carcinogenesis, especially self-renewal ability of ESCC-CSCs remains unclear. In this study, we found a high expression of DNMT1 in both side population (SP) cells and sphere formation cells that represented as substitutes for CSCs in KYSE150 and EC109 ESCC cell lines. In addition, the expression of DNMT1 was decreased during the differentiation from SP to None-SP (NSP) in these ESCC cells. These results suggested that DNMT1 might have a role in regulating self-renewal and/or differentiation of ESCC-CSCs. To further investigate DNMT1 in ESCC carcinogenesis and self-renewal ability of ESCC-CSCs, we silenced the expression of DNMT1 in KYSE150 and EC109 ESCC cells using lentivirus-mediated RNA interference (RNAi). Our results showed that ablation of DNMT1 expression in KYSE150 and EC109 ESCC cells resulted in decreased their CSCs by SP analysis and sphere formation assay. Meanwhile, ablation of DNMT1 expression inhibited malignant phenotypes in KYSE150 and EC109 cells, including cell proliferation, colony formation, migration and drug resistance abilities. Treatment of 5-aza-2'-deoxycytidine (5-aza-dC), a DNMT inhibitor that led to the degradation of DNMT1 protein by proteasome, revealed that numbers of CSCs and the malignant phenotypes of KYSE150 and EC109 ESCC cells were refrained significantly, including a dramatic inhibition of self-renewal ability of these ESCC-CSCs. Thus, our results indicated that DNMT1 was involved in ESCC carcinogenesis, especially in the maintenance of ESCC-CSCs, suggesting that DNMT1 could be a potential target for ESCC, especially ESCC-CSCs, therapy.
Citation Format: Ying Teng, Xiying Yu, Hui Yuan, Liping Guo, Wei Jiang, Shih-Hsin Lu. DNMT1 is involved in esophageal squamous cell carcinoma (ESCC) and self-renewal ability of ESCC-cancer stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1901. doi:10.1158/1538-7445.AM2017-1901
Abstract 191: Double blockade of interacting CK2 and EGFR pathways by tumor-targeting nanobioconjugates increases therapeutic efficacy against glioblastoma multiforme
Authors: Ljubimova Julia Y. 
Published: July 2017

Abstract
Introduction: Glioblastoma multiforme (GBM) remains the deadliest brain tumor in adults, and is notorious for drug and radiation resistance. To inhibit GBMs more effectively, polymalic acid-based blood-brain barrier crossing nanobioconjugates were synthesized that are delivered to the cytoplasm of cancer cells and specifically inhibit the master regulator serine/threonine protein kinase CK2 and the wild-type/mutated epidermal growth factor receptor (EGFR/EGFRvIII), which are overexpressed in gliomas according to The Cancer Genome Atlas (TCGA) GBM database.
Methods and Results: The used nanobioconjugates are novel nanotherapeutics where all moieties are covalently connected to poly(β-L-malic acid) (PMLA). Our biodegradable and non-toxic nanodrugs bind to the receptors enriched on tumor vasculature and cross the BBB by transcytosis. They specifically bind to cancer cells and after internalization exit to the tumor cell cytoplasm using pH-sensitive endosomal disruption unit. Two xenogeneic mouse models bearing intracranial human GBMs from cell lines LN229 and U87MG that expressed both CK2 and EGFR were used. The knockdown of CK2α and EGFR/EGFRvIII suppressed their downstream prosurvival signaling. Treatment also markedly reduced the expression of programmed death-ligand 1 (PD-L1), a negative regulator of cytotoxic lymphocytes. Downregulation of CK2 and EGFR also caused suppression of heat shock protein 90 (Hsp90) co-chaperone Cdc37, which may inhibit the activity of key cellular kinases. Inhibition of either target was associated with downregulation of the other target as well, which may underlie efficacy of the dual nanobioconjugate that is directed against both CK2 and EGFR. Importantly, the single nanodrugs, and especially the dual nanodrug, markedly suppressed the expression of cancer stem cell markers c-Myc, CD133, and nestin, which could contribute to the efficacy of these nanodrugs. In both tumor models, the dually targeting nanobioconjugate significantly increased (up to 2-fold) animal survival compared with the control group.
Conclusion: The versatile nanobioconjugates developed in this study, with the ability of anti-cancer drug delivery across biobarriers and inhibition of key tumor regulators, offer a promising nanotherapeutic approach to treat GBMs and to potentially prevent drug resistance and retard the brain tumor recurrence.
Support: NIH grants U01 CA151815, R01 CA136841, R01 CA188743, R01 CA209921, R01 EY013431
Citation Format: Julia Y. Ljubimova. Double blockade of interacting CK2 and EGFR pathways by tumor-targeting nanobioconjugates increases therapeutic efficacy against glioblastoma multiforme [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 191. doi:10.1158/1538-7445.AM2017-191
Abstract 1910: NF-kappaB classical versus alternative pathways support distinct populations of ovarian cancer tumor-initiating cells
Authors: House Carrie D. , Annunziata Christina M. 
Published: July 2017

Abstract
Ovarian cancer is the most lethal gynecological malignancy in the United States with high morbidity and mortality due to recurrence and chemoresistance. Our data suggest tumor-initiating cells (TICs) play an important role in disease biology. We previously showed that a subset of ovarian cancer cells depends on NF-kappaB signaling, and that expression of NF-kappaB proteins is associated with poor survival. Given that NF-kappaB expression correlates with a poor outcome in ovarian cancer, and NF-kappaB activity supports drug resistance and tumorigenicity, we hypothesize that NF-kappaB supports a TIC program responsible for ovarian cancer relapse. To investigate this pathway in TICs, we designed a novel method to enrich for TICs from cell lines and patient samples by culturing non-adherent, floating cells in stem cell conditions defined by low attachment flasks and serum free media. Preliminary data confirm that these cells have higher stem cell marker expression, are chemoresistant, and are more tumorigenic in nude mice compared to their adherent counterparts. These TIC-enriched culture conditions enhance NF-kappaB expression and activity. More specifically, alternative NF-kappaB signaling through the RelB transcription factor supports TIC populations by regulating aldehyde dehydrogenase (ALDH), an enzyme with high activity in TICs. Using an inducible shRNA targeting RelB we show that spheroid formation, ALDH expression and activity, chemoresistance, and tumorigenesis in both subcutaneous and intrabursal xenograft models, significantly decreased in the absence of RelB. Interestingly, loss of classical NF-kappaB signaling, through an shRNA targeting the RelA transcription factor, was less effective in targeting TICs, but more effective at targeting a proliferative subpopulation with high Ki67 staining. We conclude that classical and alternative NF-kappaB signaling support ovarian tumor cells with distinct phenotypes and the collaboration of these pathways may be critical for supporting tumor repopulation following chemotherapy. Current studies will measure system level changes induced by these shRNAs, and identify a gene signature specific to each NF-kappaB pathway in ovarian TICs. Clarifying the nuances of NF-kappaB signaling in TICs will increase our understanding of ovarian cancer recurrence and further focus therapeutic strategies to prevent relapse.
Citation Format: Carrie D. House, Christina M. Annunziata. NF-kappaB classical versus alternative pathways support distinct populations of ovarian cancer tumor-initiating cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1910. doi:10.1158/1538-7445.AM2017-1910
Abstract 1912: Actn4, a novel therapeutic target of dietary ellagic acid, promotes breast cancer metastasis via mediating cancer stem cells
Authors: Wang Neng , Wang Zhiyu , Xie Xiaoming 
Published: July 2017

Abstract
Purpose: Pharmacology-based target identification has become a novel stratey leading to the discovery of novel pathological biomarkers. Ellagic acid (EA), a dietary polyphenol compound, exhibits potent anticancer activities, whereas the underlying mechanisms remain unclear. This study sought to determine the role and regulation of ACTN4 expression in human breast cancer metastasis and EA-based therapy.
Experimental Design: The anti-metastasis ability of EA was validated by MMTV-PyMT mice and in vitro cell models. Drug affiity responsive target stability (DARTS) was utilized to identify ACTN4 as the direct target of EA in breast breast cancer stem cells (CSCs). The metastatic regulated mechanisms of ACTN4 were assessed by CSC-related assays including mammosphere formation, tumorigenic ability, reattachment differentiation and signaling pathway analysis. The clinical significance of ACTN4 was based on human tissue microarray analysis and TCGA database exploration.
Results: EA inhibited breast cancer growth and metastasis via directly targeting ACTN4 in vitro and in vivo, accompanied with limited CSCs population. ACTN4 knockdown resulted in blockage of malignant cell proliferation, colony formation and ameliorated metastasis potency. ACTN4 positive CSCs exhibited higher ESA+ proportion, increased mammosphere-formation ability, as well as enhanced in vivo tumorigenesis ability. Increased ACTN4 expression was directly associated with later cancer stage, increased incidence of metastasis, and poor overall survival period.
Conclusions: ACTN4 plays an important role in breast CSCs-related metastasis and is a novel therapeutic target of EA treatment.
Note: This abstract was not presented at the meeting.
Citation Format: Neng Wang, Zhiyu Wang, Xiaoming Xie. Actn4, a novel therapeutic target of dietary ellagic acid, promotes breast cancer metastasis via mediating cancer stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1912. doi:10.1158/1538-7445.AM2017-1912
Abstract 1919: Twist1 modulates paclitaxel-induced cancer stem cell enrichment in triple-negative breast cancer
Authors: Yang Aimin , He Xiaoyuan , Schulte Bradley A. , Carroll Steven L. , Ethier Stephen P. , Wang Gavin Y. 
Published: July 2017

Abstract
Triple-negative breast cancer (TNBC), the most aggressive subtype of breast cancers, is highly refractory to chemotherapy and has a high incidence of metastasis and tumor relapse. Targeted therapies for TNBC do not exist because this subtype lacks druggable hormone receptors and HER2 amplification or overexpression. Although Taxane-based chemotherapy is a standard of care for TNBC treatment, paclitaxel (Taxol)-induced cancer stem cell (CSC) enrichment presents a significant challenge to the success of breast cancer treatment. Thus, there is a critical need to understand the mechanisms by which chemotherapy induces CSC enrichment in residual tumors following anticancer therapies. Here we report that Taxol-induced enrichment for CSCs correlates well with a marked upregulation of Twist1 expression in human TNBC cells. Knockdown of Twist1 inhibits the clonogenic capacity of TNBC cells in vitro and TNBC tumorigenesis in vivo. Mammosphere formation assays indicate that silencing of Twist1 greatly diminishes the tumor sphere-forming potential of breast CSCs. Furthermore, limited dilution assays and stem cell xenotransplantation reveal that knockdown of Twist1 expression decreases the frequency of CSCs by 72-fold in human TNBC cells. More importantly, we show that silencing of Twist1 blocks Taxol-induced CSC enrichment in residual tumor cells that have survived drug treatment. Together, these results demonstrate a previously unrecognized role for Twist1 in mediating Taxol-induced CSC enrichment in residual tumors of human TNBC and suggest that targeted inhibition of the Twist1 signaling pathway may represent a novel therapeutic strategy to tackle therapy-induced CSC enrichment in breast cancer treatment.
Citation Format: Aimin Yang, Xiaoyuan He, Bradley A. Schulte, Steven L. Carroll, Stephen P. Ethier, Gavin Y. Wang. Twist1 modulates paclitaxel-induced cancer stem cell enrichment in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1919. doi:10.1158/1538-7445.AM2017-1919
Abstract 1923: Paired isolation and expansion of CSC and CTC from primary small cell lung cancer patient tissue and blood using the 3DKUBE bioreactor platform
Authors: Millard Melissa , Lotstein Alina , Holmes Lillia , Schammel David , Chung Ki , Edenfield Jeff , Crosswell Hal E. , DesRochers Tessa 
Published: July 2017

Abstract
Surgical resection is rarely an option for small cell lung cancer (SCLC) patients as the majority present with extensive disease at diagnosis. This scarcity of patient samples suitable for research presents a significant road block for the development of SCLC targeted-therapeutics. To address the problem of tissue scarcity, we have developed a method for the isolation and expansion of cancer stem cells (CSC) and circulating tumor cells (CTC) from primary tissues and blood of SCLC patients using the 3DKUBE™ perfusion microbioreactor. We have established a label-free, combined chemical and functional selection method for the isolation of CSCs from SCLC samples, solid tumor as well as blood, that does not rely upon the bias imposed by marker-based selection. Cells enriched in this manner were further purified and expanded under optimized conditions (growth factors, ECM, scaffolding and oxygen tension) within the 3DKUBE™ perfusion microbioreactor. These isolated and expanded CSCs have maintained resistance to cisplatin and etoposide, stabilized the expression of traditional CSC markers, and been validated in vitro through serial spheroid formation assays. These CSCs are currently being characterized and compared to parental tissue through correlative genomic and phenomic analysis and validated through in vivo tumorigenesis models. These cells will be utilized to generate 3D microtumors to accurately predict SCLC drug response in vitro, a determination that is not accurately performed in conventional 2D cell culture and is inhibited by both cost and time in patient-derived xenografts (PDX)
Citation Format: Melissa Millard, Alina Lotstein, Lillia Holmes, David Schammel, Ki Chung, Jeff Edenfield, Hal E. Crosswell, Tessa DesRochers. Paired isolation and expansion of CSC and CTC from primary small cell lung cancer patient tissue and blood using the 3DKUBE bioreactor platform [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1923. doi:10.1158/1538-7445.AM2017-1923