bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 582: hTERT inhibition stimulates cyclooxygenase2 (COX2) expression in cancer cells and synergizes with celecoxib to exert anti-cancer effects.
Authors: Liu Tiantian , Björkholm Magnus , Xu Dawei 
Published: August 2014

Abstract
Telomerase and telomerase reverse transcriptase (hTERT) confer cancer cells sustained proliferation and survival potentials through telomere lengthening dependent and independent activities. Targeting telomerase or hTERT is thus a novel anti-cancer strategy. However, telomerase/hTERT inhibition alone has minimal clinical efficacy. We explored the relationship between hTERT and oncogenic cyclooxygenase 2 (COX2) and evaluated the synergistic anti-cancer effects of targeting both hTERT and COX2. hTERT depletion in gastric and cervical cancer cells led to robust increases in mRNA and protein levels of COX2. The COX2 promoter activity increased substantially in hTERT-depleted cancer cells. Mechanistically, hTERT depletion led to the activation of p38 MAPK that was responsible for the stimulation of COX2 gene transcription. hTERT depletion or the COX2 inhibitor celecoxib alone did not affect gastric cancer cell survival, while their combination synergistically killed them both in vitro and in vivo. Taken together, hTERT induces COX2 expression in cancer cells and simultaneously targeting hTERT and COX2 synergistically kills cancer cells, which may help path a new avenue in telomerase-based cancer therapeutics.
Citation Format: Tiantian Liu, Magnus Björkholm, Dawei Xu. hTERT inhibition stimulates cyclooxygenase2 (COX2) expression in cancer cells and synergizes with celecoxib to exert anti-cancer effects. [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 582. doi:10.1158/1538-7445.AM2013-582
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 584: Enhanced chemosensitivity of osteosarcoma cells by telomerase-specific oncolytic adenovirus in combination therapy.
Authors: Osaki Shuhei , Sasaki Tsuyoshi , Tazawa Hiroshi , Hasei Joe , Yamakawa Yasuaki , Hashimoto Yuuri , Kunisada Toshiyuki , Urata Yasuo , Ozaki Toshifumi , Fujiwara Toshiyoshi 
Published: August 2014

Abstract
Osteosarcomas are the most common malignant bone tumors. Although the multi-agent chemotherapy has improved the long-term survival rate of osteosarcoma patients, some patients show a poor response to chemotherapy, leading to recurrence and poor prognosis. Therefore, the enhancement of chemosensitivity is required to cure patients with osteosarcomas. We recently developed a telomerase-speciﬁc replication-competent oncolytic adenovirus, Telomelysin (OBP-301), and confirmed the antitumor effect of OBP-301 in human osteosarcoma cells. A phase I clinical trial in US has also shown the safety of OBP-301 in cancer patients. In this study, we investigated whether OBP-301 enhances the antitumor effect of chemotherapeutic agents, doxorubicin and cisplatin, that are used for the treatment of osteosarcomas, and the molecular mechanism of chemotherapy- and OBP-301-mediated cell death pathway, autophagy and apoptosis, in human osteosarcoma cell lines. We used four human osteosarcoma cell lines, HOS, MNNG/HOS, 143B and SaOS2. OBP-301 is an attenuated adenovirus, in which the human telomerase reverse transcriptase (hTERT) promoter element drives expression of E1A and E1B genes, and causes tumor-selective lysis in a variety of human malignant tumor cells with high telomerase activity. OBP-301 infection enhanced the cytotoxic effect of chemotherapeutic agents and the calculation of combination index revealed the synergistic effects in all human osteosarcoma cell lines. To analyze the molecular mechanism in the synergistic effect induced by combination therapy, western blot analysis for apoptosis (PARP) and autophagy (LC3, p62) was performed. Combination of OBP-301 increased both apoptosis (the cleavage of PARP) and autophagy (conversion of LC3-I to LC3-II and p62 downregulation) in the chemotherapeutic agents-treated human osteosarcoma cells. In contrast, the replication of OBP-301 was not suppressed by chemotherapeutic agents. Moreover, combination therapy of chemotherapeutic agents with OBP-301 signiﬁcantly suppressed tumor growth in a subcutaneous xenograft tumor model compared to monotherapy with chemotherapeutic agents or OBP-301. These results suggest that combination therapy of chemotherapeutic agents with OBP-301 provides a novel therapeutic strategy for human osteosarcomas.
Citation Format: Shuhei Osaki, Tsuyoshi Sasaki, Hiroshi Tazawa, Joe Hasei, Yasuaki Yamakawa, Yuuri Hashimoto, Toshiyuki Kunisada, Yasuo Urata, Toshifumi Ozaki, Toshiyoshi Fujiwara. Enhanced chemosensitivity of osteosarcoma cells by telomerase-specific oncolytic adenovirus in combination therapy. [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 584. doi:10.1158/1538-7445.AM2013-584
Abstract 593: Embelin induces reactive oxygen species-mediated apoptosis in PTC cells.
Authors: Uddin Shahab , Ahmed Maqbool , Hussain Azhar R. , Al-Kuraya Khawla S. 
Published: August 2014

Abstract
The X-linked inhibitor of apoptosis (XIAP) is a promising new molecular target for the design of novel anticancer drugs aiming at overcoming apoptosis-resistance of cancer cells to. Recent studies demonstrated that the BIR3 domain of XIAP where caspase-9 and Smac proteins bind is an attractive site for designing small-molecule inhibitors of XIAP. Embelin, identified primarily from the Embelia ribes plant, is one such compound shown to exhibit chemopreventive, anti-inflammatory, and apoptotic activities via inhibiting XIAP activity. In this study we found tthat embelin generated a dose dependent Reactive oxygen species (ROS) in PTC cell lines. Pretreatment of PTC cell with N-acetyl-Lcysteine, an scavenger of ROS prevented embelin mediated inhibition of cell proliferation and apoptosis. Further more, NAC pretreatment also abrogated embeling mediated mitochondrial apoptosis. In addition treatment of PTC cell lines with embelin causes activation of p38, a stress related map kinases leading to up-regulation of death receptor 5 (DR5). Interestingly NAC pretreatment prevented its activation as well as up-regulation of DR5. Altogether, these data suggest a novel function for embelin causes inhibition of cell proliferation and induction of apoptosis via generation of ROS a suppressor of XIAP pathway via generation of ROS in PTC cells, and raise the possibility that this agent may have a future therapeutic role in PTC and possibly other malignancies with up-regulated XIAP pathway.
Citation Format: Shahab Uddin, Maqbool Ahmed, Azhar R. Hussain, Khawla S. Al-Kuraya. Embelin induces reactive oxygen species-mediated apoptosis in PTC 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 593. doi:10.1158/1538-7445.AM2013-593
Abstract 606: Inhibition of epithelial to mesenchymal transition and advancement of therapeutic effect in oral cancer by the flavonoid compound, Quercetin: pivotal roles of Snail repression and RKIP induction.
Authors: Chang Yun-Ching , Chiou Shih-Hwa , Nieh Shin 
Published: August 2014

Abstract
Oral squamous cell carcinoma (OSCC) is prevalent worldwide, and survival in OSCC has not improved significantly in the last few decades. Cancer prevention using natural products has become an integral part of cancer control. Quercetin is a plant-derived flavonoid known to possess anti-inflammatory property, but its use as a chemopreventive substance has been reviewed quite recently. Several reports have assessed the pro-apoptotic action of Quercetin in cancer cells similar to many other flavonoids, although the mechanisms involved are not clear. We here reported that Quercetion-mediated sensitization may result from modulation of the EMT inducer Snail and the EMT suppressor/ immunosurveillance cancer gene product Raf-1 kinase inhibitory protein (RKIP). Quercetin regulated EMT, invasion, cell survival and apoptosis via inhibition of NF-κB inactivation as well as leaded to the induction of RKIP through downregulation of its transcriptional repressor Snail. Quercetin-induced RKIP upregulation potentiates further modulated mitochondria-mediated apoptosis, thus leading to enhance therapeutic effect. These findings demonstrate the role of Quercetin in the regulation of EMT via inhibition of NF-κB and Snail and induction of RKIP and also identified Quercetin as targets for resistance via NF-κB/Snail/RKIP circuitry.
Citation Format: Yun-Ching Chang, Shih-Hwa Chiou, Shin Nieh. Inhibition of epithelial to mesenchymal transition and advancement of therapeutic effect in oral cancer by the flavonoid compound, Quercetin: pivotal roles of Snail repression and RKIP induction. [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 606. doi:10.1158/1538-7445.AM2013-606
Abstract 610: Short peptides for targeted apoptosis in cancer cells: development & evaluation of therapeutic applications.
Authors: Boyko Oleksandr , Riabowol Karl T. 
Published: August 2014

Abstract
The ING proteins are type II tumor suppressors that are involved in the regulation of gene transcription, DNA repair, cellular senescence, tumorigenesis and apoptosis. Inactivation of apoptosis pathways is frequently observed in cancer cells, and it leads to a drastic decrease in the efficiency of available cancer treatments. Inactivation of INGs during the suppression of apoptosis tumors and greater sensitivity of cancer versus normal cells to the elevation of ING1 levels suggest that the INGs could serve as viable targets for cancer therapy. In this study we expand our previous observations that all ING proteins share a conserved sequence domain, the Lamin Interacting Domain (LID), which is unique to INGs in the human proteome. The overexpression of a recombinant peptide containing multiple fragments of the LID domain was previously shown to induce apoptosis in a rapid and efficient way in several cancer cell line models. Together, rather limited knowledge of the molecular mechanisms that mediated these apoptosis-inducing effects and the large size of the recombinant LID peptide precluded use of the LID for therapeutic purposes. Here we define the minimal portion of the LID domain that is capable of efficiently inducing apoptosis, and devise approaches to efficiently introduce it into cancer cells where we predict it will show a good therapeutic index by virtue of inducing apoptosis in cancer cells much more efficiently than in normal surrounding cells. Our preliminary in silico analysis of the LID protein structure indicated that LID peptides could interfere with several “master regulators” of cell cycle control and apoptosis, including Retinoblastoma and SMAC proteins. Overexpression of LID peptides could also interfere with the formation of functional ING1-HDAC chromatin modifying protein complexes by disrupting ING1-Lamin A interactions, thus leading to the loss of HDAC targeting and apoptosis. Our ongoing studies should help to identify the molecular mechanism(s) of LID-mediated apoptosis induction and identify the minimal required sequence of LID peptide that still displays potent apoptosis-inducing activity against tumor cells. Our long term goal is to further expand current understanding of apoptosis pathways and develop LID-based therapeutic for the selective induction of apoptosis in cancer cells.
Citation Format: Oleksandr Boyko, Karl T. Riabowol. Short peptides for targeted apoptosis in cancer cells: development & evaluation of therapeutic applications. [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 610. doi:10.1158/1538-7445.AM2013-610
Abstract 611: AID/APOBEC cytidine deaminases can mimic the phenomenon of localized hypermutation in cancer or kataegis.
Authors: Nik-Zainal Serena , Taylor Ben , Wu Yee Ling , Wedge David , Rada Cristina , Stratton Mike , Neuberger Michael 
Published: August 2014

Abstract
Recently, using whole-genome sequencing data of breast cancer genomes we revealed localized regions of dense somatic hypermutation, called kataegis, in which substitutions at C:G base pairs occurring within a distinctive sequence context were found associated with clusters of genomic rearrangements. The mechanism of kataegis is unknown. On the basis of similarities in mutation class and sequence context in experimental systems, members of the AID/APOBEC family of cytidine deaminases were implicated.
Here we expressed members of this gene family in yeast and demonstrate that mutation clusters mimicking many of the features of kataegis in cancer, can be generated. Because the genomic location of each stretch of kataegis is different between individual human cancer genomes, it was reasoned that kataegis is triggered by a local stochastic event, such as a DNA double strand break. Here, we have introduced double strand breaks into the yeast genome and shown that kataegis is elicited in its vicinity. Furthermore, kataegis is substantially diminished in the absence of uracil-DNA glycosylase, indicating that base excision DNA repair is implicated in its genesis. Additionally, the mutation sequence context preferences revealed by these yeast experiments suggest that APOBEC3B and APOBEC3A are the deaminases most likely responsible for the kataegis observed in human cancer. The results therefore provide insights into the mechanism of kataegis and indicate a contribution of APOBEC3B/A-catalyzed DNA deamination to genome mutation in cancer. Finally, we show using an algorithm developed to allow efficient detection of kataegis in other publicly available whole-genome sequenced datasests that this phenomenon is not restricted to breast cancer.
Citation Format: Serena Nik-Zainal, Ben Taylor, Yee Ling Wu, David Wedge, Cristina Rada, Mike Stratton, Michael Neuberger. AID/APOBEC cytidine deaminases can mimic the phenomenon of localized hypermutation in cancer or kataegis. [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 611. doi:10.1158/1538-7445.AM2013-611
Abstract 626: DNA damage responses in different cell types of nonproliferating human prostate tissue.
Authors: af Hällström Taija M. , Jäämaa Sari , Sankila Anna , Mirtti Tuomas , Rantanen Ville , Koistinen Hannu , Stenman Ulf-Håkan , Zhang Zhewei , Yang Zhiming , De Marzo Angelo M. , Taari Kimmo , Ruutu Mirja , Andersson Leif C. , Laiho Marikki 
Published: August 2014

Abstract
DNA damage response (DDR) pathways have been extensively studied in cancer cell lines and mouse models, but little is known about how DNA damage is recognized by different cell types in nonmalignant, slowly replicating human tissues. Here, we assess, using ex vivo cultures of human prostate tissue, DDR caused by cytotoxic drugs (camptothecin, doxorubicin, etoposide, and cisplatin) and ionizing radiation (IR) in the context of normal tissue architecture. Using specific markers for basal and luminal epithelial cells, we determine and quantify cell compartment-specific damage recognition. IR, doxorubicin, and etoposide induced the phosphorylation of H2A.X on Ser(139) (gH2AX) and DNA damage foci formation. Surprisingly, luminal epithelial cells lack the prominent gH2AX response after IR when compared with basal cells, although ATM phosphorylation on Ser(1981) and 53BP1 foci were clearly detectable in both cell types. The attenuated gH2AX response seems to result from low levels of total H2A.X in the luminal cells. Marked increase in p53, a downstream target of the activated ATM pathway, was detected only in response to camptothecin and doxorubicin. These findings emphasize the diversity of pathways activated by DNA damage in slowly replicating tissues and reveal an unexpected deviation in the prostate luminal compartment that may be relevant in prostate tumorigenesis. Detailed mapping of tissue and cell type differences in DDR will provide an outlook of relevant responses to therapeutic strategies. TSC model presented can also be used for functional genomic studies, cellular and tumor biology as well as for drug response testing.
Citation Format: Taija M. af Hällström, Sari Jäämaa, Anna Sankila, Tuomas Mirtti, Ville Rantanen, Hannu Koistinen, Ulf-Håkan Stenman, Zhewei Zhang, Zhiming Yang, Angelo M. De Marzo, Kimmo Taari, Mirja Ruutu, Leif C. Andersson, Marikki Laiho. DNA damage responses in different cell types of nonproliferating human prostate tissue. [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 626. doi:10.1158/1538-7445.AM2013-626
Abstract 640: Human MutS homologue 4 (hMSH4) interacts with eIF3f and inhibits NHEJ-mediated DNA repair.
Authors: Wu Xiling , Chu Yen-Lin , Her Chengtao 
Published: August 2014

Abstract
DNA mismatch repair (MMR) proteins participate in diverse cellular functions including DNA damage response and repair. As a member of the MMR family, hMSH4 plays an important role in meiotic recombination, likely through the formation of hMSH4-hMSH5 heterocomplex that interacts with homologous recombination DNA intermediate structures. It is known that hMSH4 is expressed in an array of somatic cells; however, its involvement in mitotic processes is poorly defined. We have identified a new hMSH4 interacting partner eIF3f, a protein that functions not only in translation but also in the regulation of apoptosis and tumorigenesis. Our studies have demonstrated that hMSH4-eIF3f interaction is mediated through the N-terminal regions of both proteins. The interaction with eIF3f stabilizes hMSH4 protein, which in turn sustains DNA double strand break (DSB)-induced γ-H2AX foci and compromises cell survival in response to ionizing radiation (IR). These effects could be attributed to the inhibition of NHEJ activity by hMSH4. Furthermore, hMSH4 reduces IR-induced AKT activation, thereby facilitating eIF3f-mediated bypass of S phase arrest, and ultimately promoting G2/M arrest in response to IR treatment. In short, this study revealed a potential role of hMSH4 in the maintenance of genomic stability through suppressing error-prone DSB repair.
Citation Format: Xiling Wu, Yen-Lin Chu, Chengtao Her. Human MutS homologue 4 (hMSH4) interacts with eIF3f and inhibits NHEJ-mediated DNA repair. [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 640. doi:10.1158/1538-7445.AM2013-640
Abstract 644: Identification of a novel hypermethylated tumor suppressor gene in human bladder cancer and its implication in non-invasive cancer detection using voided urine.
Authors: Yeh Chia-Ming , Chen Pi-Che , Chen Yu-Hsin , Hung Lin-Chien , Wang Yi-Ting , Tsai Ming-Hsuan , Huang Martin MS , Shen Cheng-Huang , Hsu Cheng-Da , Chan Michael WY 
Published: August 2014

Abstract
Bladder cancer is the sixth most common cancer in the world and the incidence is particularly high in southwestern Taiwan. Although bladder cancer patients have a low mortality rate, long term follow-up with repeated cystoscopy is required due to the high recurrence nature of the tumor. Therefore, a non-invasive detection assay is urgently required for bladder cancer patients. Aberrant promoter hypermethylation which is considered as a hallmark of cancer for over a decade, plays an important role in controlling cancer progression. Nevertheless, detection of promoter hypermethylation in bodily fluid has been implicated as a non-invasive and sensitive tool for cancer diagnosis. In this regard, by using illumina 27K CpG island methylation array, we identified a novel gene that are hypermethylated in 7 bladder cancer patient samples but not in primary normal human urothelim. In vitro promoter methylation assay and epigenetic treatment confirmed that the expression of this gene is epigenetically controlled in bladder cancer cell lines. Bisulphite pyrosequencing demonstrated a significant correlation between higher methylation level of this gene and cancer grade (P&lt;0.01) and recurrence free survival (P&lt;0.05) in bladder cancer patient samples (n=100). To investigate the diagnostic potential of this novel epigenetic marker in non-invasive cancer detection, we performed qMSP assay in voided urine samples from bladder cancer patients (n=27) as well as normal healthy control (n=19). The sensitivity and specificity of this gene in cancer detection is 42.3% and 100% respectively. The sensitivity can increase to 93.3% when using combination of this gene and our previously identified epigenetic markers (IRF8, p14, sFRP1). Re-expression of this gene in bladder cancer cell line inhibited cancer growth in soft agar colony formation assay and invasion assay. In conclusion, this gene may be a potential tumor suppressor in bladder cancer and its potential in non-invasive diagnosis of bladder cancer using voided urine warrants further investigation.
Citation Format: Chia-Ming Yeh, Pi-Che Chen, Yu-Hsin Chen, Lin-Chien Hung, Yi-Ting Wang, Ming-Hsuan Tsai, Martin MS Huang, Cheng-Huang Shen, Cheng-Da Hsu, Michael WY Chan. Identification of a novel hypermethylated tumor suppressor gene in human bladder cancer and its implication in non-invasive cancer detection using voided urine. [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 644. doi:10.1158/1538-7445.AM2013-644