bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1980: Dihydroartemisinin inhibits ovarian cancer growth and metastasis via targeting PDGFRα
Authors: Li Xiaoguang , Liu Yanling , Yue Qingxi , Zhang Jianbing , Gong Nuoxi , Chen Peizhan , Liu Hong , Geng Meiyu , Qiang Fulin , Zhang Ruiwen , Wang Hui 
Published: August 2012

Abstract
Artemisinin and its analogs, the well-established clinically used anti-malarial traditional medicine, have been proven to have potent anticancer activities. We have demonstrated that Artemisinin and analogs have significant anti-ovarian cancer effect used alone or in combination with conventional chemotherapeutic agents. However, the mechanisms of action for their anticancer activities are not completely understood. Herein we report that dihydroartemisinin, one of the most active derivatives of artemisinin, directly targets platelet-derived growth factor receptor-alpha (PDGFRα) to repress ovarian cancer growth and metastasis. Dihydroartemisinin directly interacts with PDGFRα and induces dephosphorylated inactivation and ubiquitin-mediated degradation of PDGFRα, which further inactivates downstream phosphoinositide 3-kinase (PI3K) and Mitogen-Activated Protein Kinase (MAPK) pathway and subsequently represses epithelial-mesenchymal transition (EMT) in terms of upregulation of epithelial marker E-cadherin and downregulation of mesenchymal markers N-cadherin and vimentin and transcriptional repressors Snail, Twist and Slug, leading to suppression of cell growth and metastasis in PDGFRα-positive ovarian cancer cells in vitro and in vivo mouse orthotopic ovarian cancer model. These findings may contribute to the development of more effective artemisinin-based targeted compounds as novel target therapy for the treatment of human cancers.
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 1980. doi:1538-7445.AM2012-1980
Abstract 1998: Inhibition of hedgehog signaling in prostate cancer by extracts of Sutherlandia
Authors: Jackson Glenn A. , Lin Hui , Lu Yuan , Drenkhahn Sara K. , Starkey Nicholas J. E. , Huber Christal D. , Lei Wei , Rottinghaus George E. , Folk William , Browning Jim D. , Besch-Williford Cindy L. , Fritsche Kevin L. , Lubahn Dennis B. 
Published: August 2012

Abstract
Prostate cancer possesses long latency periods and is responsive to dietary mediators, making it a target for phytochemoprevention. Many botanical compounds that have been proposed to prevent cancer may potentially work via inhibition of the hedgehog signaling pathway. Here we investigated the potential of Sutherlandia frutescens (also called Lessertia and “cancer bush” in South Africa) to inhibit hedgehog signaling. We hypothesize that the anti-cancer effects of Sutherlandia are due to its inhibition of hedgehog signaling pathway activity. Methods: We evaluated Sutherlandia's effects of growth inhibition in vitro both in the human prostate cancer cell line PC3 and mouse prostate cancer cell line TRAMP-C2 by exposing the cells for 72hrs to plant extracts before protein concentrations were measured to evaluate inhibition of growth. To determine hedgehog pathway inhibitory activity, we treated two different cell lines (an NIH3T3 cell line and a TRAMPC2 cell line) stably transfected with a firefly luciferase reporter having Gli response elements in the firefly luciferase promoter. After 48hr exposure to treatment with multiple doses of Sutherlandia, a firefly substrate was added to the cell lysate and the luciferase signal was measured using a Biotek Synergy plate reader. Finally, Sutherlandia was incorporated into a diet and fed to TRAMP (Transgenic Adenocarcinoma Mouse Prostate) mice to examine whether the plant can delay or even inhibit prostate cancer incidence in the TRAMPmouse model. Results: Sutherlandia extracts inhibited growth of both PC3 and TRAMPC2 cells. In addition, hedgehog signaling was inhibited by Sutherlandia in both NIH3T3 and TRAMPC2 reporter cells. Interestingly, in vivo the lowest concentration of Sutherlandia diet had the greatest effect on inhibition of poorly differentiated adenocarcinoma in the TRAMP mice. Conclusions: Sutherlandia's inhibition of prostate cancer growth may be via inhibition of hedgehog signaling. Future work to identify in Sutherlandia the active compound having this effect, and the ideal concentration for use in vivo may lead to a means whereby dietary intervention for prostate cancer prevention and/or treatment is possible.
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 1998. doi:1538-7445.AM2012-1998
Abstract 2002: OCT-3/4 expression is associated with high levels of the pro-apoptotic BH3 only protein NOXA in testicular germ cell tumors (TGCTs)
Authors: Gutekunst Matthias , Mueller Thomas , Weilbacher Andrea , Dengler Michael A. , Kruck Stephan , Bedke Jens , Aulitzky Walter E. , van der Kuip Heiko 
Published: August 2012

Abstract
Embryonal carcinoma (EC) cells are the pluripotent precursors of differentiated structures of testicular germ cell tumors (TGCT) characterized by expression of the embryonal transcription factor OCT-3/4. Loss of OCT-3/4 during differentiation abrogates the extraordinary high sensitivity to cisplatin in these cells. We previously observed a constitutively high expression level of NOXA and a major role of this pro-apoptotic BH3-only protein for cisplatin hypersensitivity in the EC cell lines NTERA-2D1 and 2102EP. We now investigated if these high NOXA protein levels may be directly linked to the OCT-3/4 status in TGCT cells. Therefore, we analyzed NOXA protein expression in an extended TGCT cell line panel of 5 OCT-3/4 negative and 5 OCT-3/4 positive cell lines. Importantly, NOXA protein was highly correlated with OCT-3/4 levels and also with cisplatin sensitivity. These data indicate that constitutively high NOXA levels might be responsible for the low threshold for cisplatin-induced apoptosis in OCT-3/4 positive pluripotent cells. A direct link between OCT-3/4 and NOXA could also be demonstrated by RNAi mediated silencing experiments performed in NTERA-2D1 and 2102EP cells. Silencing of OCT-3/4 resulted in a significant downregulation of NOXA transcript and an almost complete loss of NOXA protein accompanied by a loss of cisplatin sensitivity. This was observed in both differentiation competent NTERA-2D1 cells as well as in differentiation incompetent 2102EP cells pointing to a direct OCT-3/4 dependent NOXA regulation rather than a bystander effect of differentiation upon loss of OCT-3/4. We further validated our in vitro data by comparing OCT-3/4 and NOXA expression levels in patient samples derived from ECs with other non-seminomatous GCTs, seminomas, and tumor entities from lung, breast, and ovary. In agreement with our in vitro observations, OCT-3/4 and NOXA were found to be highly expressed selectively in seminomas and ECs. This could also be confirmed on protein level in primary tissue samples derived from 5 ECs and 8 seminomas by western blot analysis. In conclusion, our data for the first time demonstrate a close correlation between OCT-3/4 and NOXA protein levels and strengthen the previously hypothesized role of constitutively high NOXA levels for the exquisite sensitivity of TGCTs to cisplatin.
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 2002. doi:1538-7445.AM2012-2002
Abstract 2003: STAT3 is a critical mediator of the pro-survival effect of Bcl-2-Rac1 interaction in human cancer cells
Authors: Kang Jia , Vali Shireen , Kapoor Shweta , Abbasi Taher , Pervaiz Shazib 
Published: August 2012

Abstract
We recently showed that Bcl-2 overexpression induced a pro-oxidant intracellular milieu resulting in an inhibition of apoptotic execution and that reversing the pro-oxidant milieu by inhibiting intracellular superoxide production sensitized Bcl-2-overexpressing cells to apoptotic stimuli. We provide evidence that the small GTPase Rac1 is functionally involved since gene silencing and functional inhibition of Rac1 blocked Bcl-2-mediated increase in intracellular superoxide production in tumor cells. A co-localization and physical interaction between the two proteins were observed, which could be blocked by the BH3 mimetics as well as by synthetic Bcl-2 BH3 domain peptides both in vitro and in vivo. The Bcl-2 BH3 peptides as well as silencing and functional inhibition of Rac1 reversed intracellular superoxide levels and overcame Bcl-2-mediated drug resistance in human leukemia and cervical cancer cells, demonstrating that this interaction is functionally relevant. Notably, the interaction was observed in primary cells from patients diagnosed with B-cell lymphoma with Bcl-2 overexpression but not in noncancerous tissue. Furthermore, computer simulation driven virtual predictive experiments based on the protein pathway dynamic network created by Cellworks Group Inc. were carried out to study the functional implication of this interaction. An HCT116 human colorectal cancer cell line with KRAS over-activation, PI3K overexpression, CDKN2A deletion, β-catenin overexpression and Bcl-2 overexpression was created as a base line. Phenotypic indices of angiogenesis, proliferation, viability, metastasis as well as tumor volume were all found to be amplified in a variant cell line when Rac1 was overexpressed based on the above computer modeled HCT116. Strikingly, the expression levels of both STAT3 and β-catenin were significantly upregulated in the variant cell line; however upon Rac1 or Bcl-2 knockdown in both the base and the variant cell lines, apoptotic markers such as Bax, caspase 3 and cleaved PARP1 were amplified while STAT3 and β-catenin were significantly down-regulated. Intrigued by these predictions, we set out to verify the correlation between STAT3 signaling and Bcl-2-Rac1 interaction. Interestingly, there is indeed a strong correlation between the activation status of STAT3 (pY705) and Bcl-2 expression as well as Rac1 activation status. Furthermore, STAT3 was found to be localized to mitochondria and our preliminary results suggest an association with Bcl-2.
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 2003. doi:1538-7445.AM2012-2003
Abstract 2005: Identification of Bcl2L13 as a novel GBM oncoprotein
Authors: Jensen Samuel A. , Calvert Andrea , Luciano Janina , Stegh Alexander 
Published: August 2012

Abstract
Using in silico analysis of 272 GBM samples in the TGCA data set to find important cell death mechanisms in gliomapathogenesis, we identified differential expression of the novel Bcl2-Like13 protein (Bcl2L13). Bcl2L13 shares significant structural homology with Bcl-2 and Bcl-xL, but contains a unique 250 amino acid sequence that may point to unique, non-classical functions. Several studies have shown that Bcl2L13 expression correlates with increased chemotherapeutic resistance and unfavorable treatment outcome in leukemia and ZIC1-driven liposarcomas. These clinical data suggests that Bcl2L13 likely acts as an onco-protein in multiple cancers and may act in a similar manner in GBM. Using qRT-PCR and immunohistochemical analyses, we found that Bcl2L13 was highly overexpressed in &gt;90% of GBM samples, but absent in adjacent normal brain. Using RNAi-loss- and cDNA complementation studies in glioma cell lines and glioma stem cells (GSCs), we determined that Bcl2L13 potently inhibits therapy-induced apoptosis by inhibiting mitochondrial outer membrane permeabalization (MOMP) and post-mitochondrial caspase-3 and -7 cleavage, likely acting in a similar manner as canonical Bcl-2 family proteins. Bcl2L13 overexpression also greatly increased cellular proliferation, and immunofluorescence and cell fractionalization experiments revealed that Bcl2L13 is localized at the mitochondria. To study the impact of Bcl2L13 on the progression of gliomagenesis in vivo, we orthotopically injected glioma cell lines with enforced expression of Bcl2L13-targeting shRNAs into immunocompromised SCID mice. Strikingly, neutralization of Bcl2L13 signaling increased overall glioma-free survival, which was associated with enhanced intratumoral apoptosis and decreased proliferative indices. To molecularly elucidate the mechanism by which Bcl2L13 exerts its anti-apoptotic effects, we performed a Yeast Two Hybrid screen and identified a select number of tumor suppressors and onco-proteins including ceramide synthase 2 (CerS2), (a regulator of MOMP) and O-6-methylguanine-DNA methyltransferase (MGMT), (an important prognostic indicator of telozolomide effectiveness) as Bcl2L13 interaction partners. Co-immunoprecipitations confirmed the interactions between Bcl2L13 and these proteins. Taken together, these results reveal that Bcl2L13 represents a novel anti-apoptotic, Bcl-2-like GBM oncoprotein that inhibits apoptosis progression and promotes tumor growth by impacting mitochondrial membrane physiology.
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 2005. doi:1538-7445.AM2012-2005
Abstract 2025: Blockade of the Shh pathway by KAAD-Cyclopamine promoted apoptosis in estrogen treated breast cancer cells
Authors: na Kang Han , An Hyun Sook , Kang Myoung Hee , Kim Jung Lim , Kim Jun Suk , Seo Jea Hong 
Published: August 2012

Abstract
The Hedgehog (Hh) signaling pathway functions as an organizer in embryonic development. Recent studies have shown constitutive activation of the hedgehog pathway is important in the development of various carcinomas including breast cancer. However, it remains unclear whether this pathway is activated in human breast cancer. Herein, we investigated the role of Shh signaling pathway in tumorigenesis of estrogen treated breast cancer cells and the molecular mechanisms underlying these effects. We showed that breast cancer cell lines express all the components of Shh signaling, albeit to different extents. Moreover, in breast cancer cells, estrogen supplementation triggered Shh up-regulation. This estrogen treated Shh expression activated the Hh pathway in a ligand-dependent manner, and increased cell proliferation. Cell proliferation was done MTT assay with various concentrations of KAAD-Cyclopamine for 24, 48, or 72 h. As a result, KAAD-Cyclopamine had anti-proliferative effect on estrogen treated breast cancer cells. Also, to determine whether the cytotoxicity induced by KAAD-Cyclopamine was due to apoptosis in estrogen-induced breast cancer cells, we measured cell cycle and the fraction of early apoptosis [Annexin V(+)/PI(-)]. Cell cycle analysis by FACS indicated that Cyclopamine treated cell lines showed an increase in the proportion of cells in sub-G1 phase, compared to untreated cells. Exposure of gastric cancer cells to Cyclopamine also resulted in the increase in the percentage of annexin V- positive and PI-negative cells. These observations demonstrate that KAAD-Cyclopamine can inhibit estrogen-induced breast cancer cell cycle progression and promote cell apoptosis. Furthermore, Western blotting analysis was used to investigate the effect of KAAD-Cyclopamine (a Shh signaling inhibitor) on estroen treated breast cancer cells. As a result, expression of cleaved PARP, caspase-3, and -9, Bax was increased. In addition, phosphorylation of Akt and of glycogensynthase kinase 3β (GSK-3β) was also reduced by treatment with KAAD-Cyclopamine. These results, taken together, suggest that Blockade of the Shh pathway by KAAD-Cyclopamine promoted apoptosis in estrogen treated breast cancer cells.
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 2025. doi:1538-7445.AM2012-2025
Abstract 2039: Human Stn1 protects telomere integrity by promoting efficient lagging strand synthesis at telomeres
Authors: Huang Chenhui , Dai Xueyu , Chai Weihang 
Published: August 2012

Abstract
Telomeres, the chromosomal termini, are critical for maintaining genome stability. The length of telomere is regulated by multiple genes including telomere-specific shelterin proteins and telomere non-specific proteins such as DNA replication proteins. Stn1, a component of the newly identified Ctc1/Stn1/Ten1 complex, is also known as (DNA polymerase) α-accessory factor AAF44 and plays an unclear role in telomere maintenance. In our studies, Stn1 depletion causes elongated G-overhang and persistent ssDNA at G-rich strand in both telomerase-positive and negative cells. Furthermore, Stn1 depletion shows an increase of fragile telomeres in strands replicated by lagging strand synthesis, implicating that Stn1 is important in efficient replication of lagging strand telomeres. Consistently, BrdU incorporation into lagging telomeres is reduced when Stn1 is depleted. In addition, Stn1 depletion leads to rapid telomere shortening. Examination of the cell cycle-regulated G-overhang dynamics showed that deficiency of hStn1 delays and compromises C-strand synthesis that occurs in the late S/G2 phase, leading to persistent lengthening of G-overhangs at lagging daughter telomeres. We also found that Stn1 interacts with Polα throughout the cycle. ChIP experiments showed that Stn1 depletion results in increased and prolonged Polα association with telomeres, but does not affect the association of Pot1 with telomeres. Our data indicate a key role of Stn1 in telomere replication and maintenance.
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 2039. doi:1538-7445.AM2012-2039
Abstract 2043: Deregulated Cdc7/Dbf4 expression promotes DNA repair and checkpoint recovery to enhance survival and associates with poor prognosis in OSCC
Authors: Cheng An Ning , Lo Yu-Kang , Jiang Shih Sheng , Lee Alan Yueh-Luen 
Published: August 2012

Abstract
Cdc7 (DDK, Dbf4-dependent kinase) is a serine-threonine kinase and required to initiate DNA replication from each origin. Although Cdc7 and Dbf4 has been shown overexpressed in many human cancer cell lines and certain primary tumors, only few cancer tissue samples were analyzed. In this report, in light of the biological, prognostic, and therapeutic implications of Cdc7 in tumorigenesis, we investigated and found that Cdc7 is overexpressed specifically in malignant non-small-cell lung cancer (NSCLC), colorectal cancer and oral squamous cell carcinoma (OSCC) tissues and Cdc7 expression level is an independent prognosis factor for patient survival in OSCC. Cdc7 is required for DNA replication and higher Cdc7 level is linked to the development of tumor cells, however, increased Cdc7 expression levels do not always correlate with the proliferative status of the tumor cells. Therefore, the underlying mechanism of overexpressed Cdc7/Dbf4 in promoting tumorigenesis still needs to be clarified. Our data suggest that up-regulation of Cdc7 has several roles in promoting tumorigenesis. First, overexpression of Cdc7 promotes cell survival through inhibiting DNA damage-induced cell apoptosis and inducing HR DNA repair. Second, during the early stage, it causes checkpoint activation as well as slow-down of S phase progression and promotes HR DNA repair that may through DSB-mediated mechanism. Third, during the late stage, upon removal of DNA lesions and completion of DNA repair in S-phase, Cdc7 attenuates checkpoint signaling and reactivates DNA replication by promoting the loading of replication initiation proteins Cdc45 as well as the activation of Plk1, which will be important for checkpoint recovery and replication restart. In summary, we have shown that a highly significant association between Cdc7 expression and overall survival in OSCC patient, rendering the prognostic importance and clinical practicability of Cdc7 expression in OSCC. Our studies also indicate that increased Cdc7 expression promotes HR repair and attenuates ATM/ATR checkpoint signaling for recovery of damaged replication forks to enhance the survival of DNA damaging agent-treated tumor cells. These studies will open an avenue to the biological, prognostic, and therapeutic applications of Cdc7 kinase in cancer therapy.
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 2043. doi:1538-7445.AM2012-2043
Abstract 2051: Inhibitors against CHK1 and WEE1, MK-8776 and MK-1775, strongly synergize in vitro and in vivo to inhibit tumor growth
Authors: Shumway Stuart D. , Guertin Amy D. , Martin Melissa M. , Roberts Brian , Hurd Melissa S. , Qu Xianlu , Miselis Nathan R. , Bloecher Andrew , Toniatti Carlo 
Published: August 2012

Abstract
Inhibitors of the checkpoint kinases CHK1 and WEE1 are under development as sensitizers to chemotherapy or radiation therapy. Disruption of either CHK1 or WEE1 activity compromises the cell cycle arrest that normally accompanies the DNA damage response, forcing cells to prematurely divide before repairing damaged DNA. However, inhibition of either CHK1 or WEE1 alone also disrupts DNA replication, resulting in DNA double strand breaks (DSBs) primarily in S-phase cells. Here we describe the ability of inhibitors against CHK1 and WEE1 to synergize both in vitro and in vivo. MK-8776 and MK-1775 are advancing through early clinical trials as potent and selective inhibitors of CHK1 and WEE1, respectively. MK-8776 increases the cell-based potency of MK-1775 in multiple cancer cell lines by as much as a 10-fold EC50 shift in proliferation assays. Staining for the DSB marker γH2AX at low concentrations of each drug demonstrates that MK-8776 and MK-1775 in combination induce up to 50-fold more DNA damage than either MK-8776 or MK-1775 alone. The ability of the combination to drive premature mitosis, determined by pHH3 quantitation, was variable, suggesting that generation of DSBs rather than G2/M checkpoint abrogation is the mechanism underlying combination cytotoxicity. Induction of DSBs requires cyclin-dependent kinase activity and takes place largely in S-phase cells, implying deregulation of DNA replication. Furthermore, staining for DNA damage response markers γH2AX and pCHK1-ser345 was both more intense and more durable in a LoVo xenograft model of cancer when MK-8776 and MK-1775 were dosed together compared to either compound alone. At tolerated doses, the combination demonstrated significantly greater anti-tumor efficacy than either MK-8776 or MK-1775 alone in LoVo xenografts (91% tumor growth inhibition for the combination versus 28% and 41% for MK-8776 and MK-1775, respectively). Similar observations were made in additional xenograft models. These results demonstrate in vitro and in vivo synergy between MK-8776 and MK-1775, indicating unique and complimentary anti-tumor effects of CHK1 and WEE1 inhibition. Our studies provide preclinical rationale for combining WEE1 and CHK1 inhibitors as a novel cancer treatment regimen.
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 2051. doi:1538-7445.AM2012-2051