bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2309: Acetylation of survivin represses transactivation of STAT3 to induce sodium butyrate-induced apoptosis in human mucoepidermoid carcinoma cell lines
Authors: Cho Sung-Dae 
Published: July 2017

Abstract
Sodium butyrate (NaBu) is one of histone deacetylase inhibitors and possesses anticancer activity. Here, the aim of this study is to determine the molecular mechanism by which NaBu controls apoptosis in MC3 and YD15 human mucoepidermoid carcinoma (MEC) cell lines. NaBu caused growth inhibition and induced apoptosis in both cell lines accompanied by the acetylation of histone proteins H2A and H3. NaBu clearly increased survivin and cleaved caspase 3 evidenced by human apoptosis array and it regulated survivin molecule at a post-transcriptional level. NaBu caused nuclear translocation of survivin protein and increased survivin acetylation in both cell lines. In addition, STAT3 and survivin were co-localized in nucleus by NaBu resulting in the decrease in the expression level of Bcl-XL mRNA which is one of STAT3 downstream molecules. In addition, NaBu induced caspase-dependent apoptosis in human MEC cells. Taken together, these results suggest that NaBu is a potent apoptosis inducer in human MEC cell lines through survivin-STAT3 signaling cascades and these findings provide the basis of its clinical application for the treatment of human MEC.
This abstract is supported by SNU Invitation Program for Distinguished Scholar and the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2014R1A12055874)
Citation Format: Sung-Dae Cho. Acetylation of survivin represses transactivation of STAT3 to induce sodium butyrate-induced apoptosis in human mucoepidermoid carcinoma cell lines [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 2309. doi:10.1158/1538-7445.AM2017-2309
Abstract 2311: A peptide derived from a photosynthetic cupredoxin protein, auracyanin, induces a p53-independent apoptosis in cancer cells
Authors: Naffouje Samer A. , Yamada Tohru , Gupta Tapas K. Das 
Published: July 2017

Abstract
Cupredoxins are a family of low-molecular weight, water soluble, copper-containing redox proteins involved mainly in the electron transfer chain in prokaryotes. Azurin is a member of the cupredoxin family secreted by Pseudomonas aeruginosa, of which a 28-amino acid sequence (p28) was identified to acquire the capability of preferential entry into cancer cells of various histogenesis. Upon entry, it exerts a cytostatic effect in these cancer cells via a p53-mediated pathway. Our aim was to study whether the other members of the cupredoxin family possess a similar function to that of azurin in the eukaryotic cancer cells. Based on structural and sequence analyses, helical regions of auracyanin A & B were shown to resemble p28 closely. Thus, we studied the biologic function of two 28-amino-acid peptides derived from auracyanin A (aurA; pI 4.5, MW 2.6 kD), and auracyanin B (aurB; pI 3.4, MW 2.7 kD). Cancer growth and MTT assays demonstrated that aurB, but not aurA, induced cytotoxicity in various cancer cell lines in a dose-dependent (range 0.1uM-100uM) and time-dependent (~72 hours) pattern, including p53-null (prostate cancer PC-3) and dn-p53 (breast cancer MDD-2 and ovarian cancer SKOV-3) in which p28 did not demonstrate a significant growth inhibition. Annexin-V assays showed a dose-dependent apoptosis in prostate cancer cell lines of various p53 statuses (wt-p53 LNCaP, mut-p53 DU-145, p53-null PC-3) following treatment with aurB at 5-50uM for 48 hours, whereas p28 did not demonstrate an apoptotic activity in p53-null cell lines, suggesting an aurB-induced apoptosis via a p53-indepdnent pathway. In contrast, aurA did not appear to induce apoptosis in any of the above cell lines. Induction of apoptosis was mediated through depolarization of the mitochondrial membrane and caspase cascade activation in cancer cells. Moreover, fluorescence microscopy demonstrated that aurB, unlike p28, does not acquire a similar pattern of preferential entry into cancer cells. This proposes that aurB acquires the potential as an anticancer cell penetrating peptide, and differs from p28 in its mode of entry and p53-mediated action. Our studies pertaining to azurin and auracyanin, suggest that cupredoxins, as a family of prokaryotic metalloproteins, could represent a fountainhead of numerous derived peptides that hold promise as novel and efficient antineoplastic agents against various cancer cell lines.
Citation Format: Samer A. Naffouje, Tohru Yamada, Tapas K. Das Gupta. A peptide derived from a photosynthetic cupredoxin protein, auracyanin, induces a p53-independent apoptosis in cancer 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 2311. doi:10.1158/1538-7445.AM2017-2311
Abstract 2315: Overcoming treatment resistance in cisplatin-resistant ovarian carcinoma cells by tissue-specific miRNAs
Authors: Kleemann Michael , Bereuther Jeremias , Fischer Simon , Marquart Kim , Hänle Simon , Unger Kristian , Jendrossek Verena , Riedel Christian U. , Handrick René , Otte Kerstin 
Published: July 2017

Abstract
Ovarian cancer is a common human cancer with a poor outcome and a high risk of death. Due to resistances to current standard therapies (carboplatin and paclitaxel for 3 to 6 cycles) additional therapeutic approaches are required and novel specific biomarkers for ovarian cancer patients are necessary. MicroRNAs (miRNA) are conserved, small noncoding RNAs regulating gene expression by binding to their target mRNA which have been shown to regulate biological processes including apoptosis. Apoptosis is a conserved, irreversible process that allows cells to undergo a highly regulated form of cell death. However, the final role of miRNAs in apoptotic signaling has not yet been fully determined. Modulating the expression of key molecular components of the cell death machinery is an attractive strategy for cancer therapy overcoming chemo drug resistance. To extend the pool of potential miRNA as anticancer agents and biomarkers, we transferred a high content miRNA screening for pro-apoptotic miRNAs to human cancer cell lines. Based on the high recovery rate of apoptosis inducing miRNAs in SKOV3 cells analyses were extended to multiple ovarian carcinoma cell lines with different genetic background. After transfection of miR-1912-5p the apoptosis rate increased strongly in cisplatin-resistant cells. In combination treatment with carboplatin the apoptotic effect increased after transfection of miR-1912-5p in the cisplatin-resistant A2780 cells. Furthermore, miR-1912-5p, miR-147b and miR-3073a showed significant apoptosis induction in the various ovarian cancer cell lines alone and in combined therapy with carboplatin. Western Blot analysis revealed an enhanced expression of the pro-apoptotic proteins Bak1 and Bax and a decrease inBcl2 and Bcl-xL. We characterized the miRNAs in regard to their endogenous expression and detected an enhanced expression after apoptosis induction by chemotherapeutic drugs. Finally, analysis of The Cancer Genome Atlas data showed an influence on the median survival of ovarian cancer patients (&gt; 69 years). Our data indicate a potential benefit of tissue specific pro-apoptotic miRNAs in regard to cisplatin-resistant cells. Furthermore the study identified novel pro-apoptotic miRNAs with their potential use as novel therapeutic entities or prognostic biomarkers for ovarian cancer.
Citation Format: Michael Kleemann, Jeremias Bereuther, Simon Fischer, Kim Marquart, Simon Hänle, Kristian Unger, Verena Jendrossek, Christian U. Riedel, René Handrick, Kerstin Otte. Overcoming treatment resistance in cisplatin-resistant ovarian carcinoma cells by tissue-specific miRNAs [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 2315. doi:10.1158/1538-7445.AM2017-2315
Abstract 2316: Elevated H-Ras suppresses death receptor-mediated apoptosis in cancer cells
Authors: Kim Su-Ryun 
Published: July 2017

Abstract
TNF-related apoptosis inducing ligand (TRAIL) induces apoptosis through its death receptors (DRs) 4 and/or 5 expressed on the surface of target cells. Despite its selectivity in killing cancer cells over most normal cells, recombinant human TRAIL or its receptor agonists (monoclonal antibodies against DR4 or DR5) encountered resistance in many tumor cells while the underlying mechanisms remain partially understood. Here, we show that wild-type H-Ras GTPase is systemically upregulated in TRAIL-resistant cells compared to TRAIL-sensitive cells. The elevated H-Ras expression correlated with a deficiency of DR4 and DR5 on plasma membrane in TRAIL-resistant cell lines. Notably, knockdown of H-Ras in TRAIL-resistant cells successfully restored the surface expression of DR4 and DR5, thereby sensitizing the cells to TRAIL-induced apoptosis. Consistently, ectopic expression of H-Ras in TRAIL-sensitive cells reduced surface DR4 and DR5 which was associated with a loss of TRAIL sensitivity. By contrast, the status of K-Ras or its mutations was not casually linked to TRAIL receptor expression or TRAIL sensitivity across the panel of cancer cell lines tested. These data suggest that H-Ras may play a distinct role to negatively regulate TRAIL receptors and apoptosis. The upregulated H-Ras could be a predictor of tumor resistance to DR-targeted agents and a potential therapeutic target for combinational therapy to achieve better treatment outcomes.
Citation Format: Su-Ryun Kim. Elevated H-Ras suppresses death receptor-mediated apoptosis in cancer 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 2316. doi:10.1158/1538-7445.AM2017-2316
Abstract 2320: Cucurbitacin D induces cell cycle arrest and apoptosis by inhibiting STAT3 and NF-κB signaling in doxorubicin-resistant human breast carcinoma (MCF7/ADR) cells
Authors: Ku Jin Mo , Hong Se Hyang , Kim Myeong-Sun , Kim Hyo In , Kang Soo-Yeon , Lee Kangwook , Choi Yu-Jeong , Cheon Chunhoo , HUANG CHING WEN , Ko Youme , Sasaki Yui , Kang Sohyeon , Kim Ji Hye , Seo Hye Sook , Kim Tai Young , Shin Yong Cheol , Ko Seong-Gyu 
Published: July 2017

Abstract
Objective: We examined whether cucurbitacin D affects doxorubicin resistance of MCF7/ADR breast cancer cells.
Methods: Cell viability was measured by MTT assay. Levels of p-STAT3, p-NF-κB, IκB, and caspases were measured by western blot analysis. Nuclear staining of Stat3 and NF-κB was measured by immunocytochemistry. STAT3 and NF-κB transcriptional activity was detected by STAT3 and NF-κB luciferase reporter gene assays. Analysis of cell cycle arrest was performed by flow cytometry. Induction of apoptosis by cucurbitacin D was measured by annexin VFITC/PI assay.
Results: More than 90% of MCF7/ADR cells lived upon treatment with doxorubicin for 24 h. However, upon treatment with cucurbitacin D, cell death was more than 60%. Co-administration of cucurbitacin D and doxorubicin induced apoptosis, G2/M cell cycle arrest, and inhibited upregulated Stat3 by doxorubicin on MCF7/ADR cells. Additionally, cucurbitacin D led to an increase in the IκBα level in the cytosol and a decrease in the p-NF-κB level in the nucleus. Finally, cucurbitacin D inhibited translocation of Stat3 and NF-κB and decreased transcriptional activity in the nucleus.
Conclusion: Cucurbitacin D decreases cell proliferation and induces apoptosis by inhibiting Stat3 and NF-κB signaling in doxorubicin-resistant breast cancer cells. Cucurbitacin D could be used as a useful compound to treat Adriamycin-resistant patients.
Note: This abstract was not presented at the meeting.
Citation Format: Jin Mo Ku, Se Hyang Hong, Myeong-Sun Kim, Hyo In Kim, Soo-Yeon Kang, Kangwook Lee, Yu-Jeong Choi, Chunhoo Cheon, CHING WEN HUANG, Youme Ko, Yui Sasaki, Sohyeon Kang, Ji Hye Kim, Hye Sook Seo, Tai Young Kim, Yong Cheol Shin, Seong-Gyu Ko. Cucurbitacin D induces cell cycle arrest and apoptosis by inhibiting STAT3 and NF-κB signaling in doxorubicin-resistant human breast carcinoma (MCF7/ADR) 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 2320. doi:10.1158/1538-7445.AM2017-2320
Abstract 2322: Antitumor activity of spicatoside A, a steroidal saponin, via induction of switch from autophagy to apoptotic cell death
Authors: Kim Won Kyung , Pyee Yuna , Park Hyen Joo , Hong Ji-Young , Lee Sang Kook 
Published: July 2017

Abstract
The antitumor activity of spicatoside A (SA), a steroidal saponin isolated from the tuber of Liriope platyphylla (Liliaceae), and its underlying mechanisms were investigated in HCT116 human colorectal cancer cells. SA induced autophagy and apoptotic cell death and inhibited tumor growth in a nude mouse xenograft model implanted with HCT116 cells. Treatment with SA for 24 h enhanced the formation of acidic vesicular organelles in the cytoplasm, indicating the induction of the onset of autophagy. This event was associated with the regulation of autophagic markers including microtubule-associated protein 1 light chain 3 (LC3)-II, p62, beclin 1, lysosomal-associated membrane protein 1, and cathepsin D by inhibiting the PI3K/Akt/mTOR signaling pathway, regulating mitogen-activated protein kinase signaling, and increasing p53 levels. However, a prolonged exposure to SA resulted in apoptosis characterized by the accumulation of a sub-G1 cell population and an annexin V/propidium iodide-positive cell population. Apoptosis induced by SA was associated with the regulation of apoptotic proteins including Bcl-2, Bax, and Bid, the release of cytochrome c into the cytosol, and the accumulation of cleaved poly ADP-ribose polymerase (PARP). Further study revealed that cleavage of beclin 1 by caspase-8 plays a critical role in the SA-mediated switch from autophagy to apoptosis. Taken together, these findings highlight the significance of SA in the modulation of crosstalk between autophagy and apoptosis, as well as the potential use of SA as a novel candidate in the treatment of human colorectal cancer cells. Acknowledgement: This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean Government (MEST) (No. 2009-0083533)
Citation Format: Won Kyung Kim, Yuna Pyee, Hyen Joo Park, Ji-Young Hong, Sang Kook Lee. Antitumor activity of spicatoside A, a steroidal saponin, via induction of switch from autophagy to apoptotic cell death [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 2322. doi:10.1158/1538-7445.AM2017-2322
Abstract 2326: A high-throughput screen identified cancer selective small molecules that kill independent of mitochondrial apoptosis
Authors: Dowling Catriona M. , Hemann Micheal , Bradner James , Letai Anthony , Chonghaile Triona Ni 
Published: July 2017

Abstract
Triple negative breast cancer (TNBC) lacks expression of oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor 2 (HER2). Importantly, there have been fewer advances in the treatment of TNBC with the mainstay of treatment being cytotoxic chemotherapy. All too often though tumor responds poorly to chemotherapy, or relapse and resistance follow an initial response. We previously found in a range of hematological and solid tumors that chemoresistant cancers are far from the mitochondrial apoptotic threshold. To identify novel therapeutics for the treatment of chemoresistant breast cancer, we performed a high-throughput screen to identify small molecules that are cancer selective but can kill independent of the mitochondrial pathway of apoptosis. To perform this screen we used TNBC line MDA-MB-231 in which the pro-death proteins BAX/BAK were knocked down. BAX/BAK are essential for mitochondrial apoptosis. To enrich for compounds that were not non-specifically toxic, we simultaneously counter-screened against the non-transformed breast epithelial cell line MCF10a. We screened a total of 30,000 compounds in duplicate across the two cell lines. There was a hit rate of 0.3% in the screen and 85 compounds were retested in the validation cherry pick screen. From the cherry pick screen 18 compounds were further validated with low-throughput assessment for mitochondrial independent killing and selectivity for cancer cells. To identify the mechanism of action of the lead compound we used a genetic approach to generate an RNAi signature for the compound. This signature enables classification of the compound into known or novel class of compounds. The lead compound signature was most like that of histone deacetylase inhibitors (HDAC). Using an in vitro HDAC inhibitor screen, we identified that the compound selectively inhibited HDAC6. Importantly, we validated that the lead compound caused an increase in acetylated tubulin in cells, a target of HDAC6. In conclusion, we have identified a novel HDAC6 specific inhibitor that selectively kills cancer cells independent of mitochondrial apoptosis.
Citation Format: Catriona M. Dowling, Micheal Hemann, James Bradner, Anthony Letai, Triona Ni Chonghaile. A high-throughput screen identified cancer selective small molecules that kill independent of mitochondrial apoptosis [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 2326. doi:10.1158/1538-7445.AM2017-2326
Abstract 2333: Modulation of Bax and mTOR for cancer therapeutics
Authors: Li Rui , Ding Chunyong , Zhang Jun , Xie Maohua , Park Dongkyoo , Ding Ye , Chen Guo , Zhang Guojing , Gilbert-Ross Melissa , Zhou Wei , Marcus Adam , Sun Shi-Yong , Chen Zhuo , Sica Gabriel , Ramalingam Suresh , Magis Andrew , Fu Haian , Khuri Fadlo , Curran Walter , Owonikoko Taofeek , Shin Dong , Zhou Jia , Deng Xingming 
Published: July 2017

Abstract
Pharmacologic manipulation of the serine (S)184 phosphorylation site of Bax protein to functionally regulate its proapoptotic activity is an attractive anticancer strategy. We recently identified three small molecule Bax agonists. SMBA1 was selected as the lead compound based on its chemical structure and its drug-like properties, from which a more effective analog, CYD-2-11, was generated. CYD-2-11 targets the structural pocket around S184 in the C-terminal tail of Bax, directly activating its proapoptotic activity via 6A7 conformational change and formation of Bax homo-oligomers in mitochondrial membranes. CYD-2-11 suppresses tumor growth in SCLC, NSCLC and patient-derived lung cancer xenografts as well as the genetically engineered mutant KRAS-driven lung cancer model with no significant normal tissue toxicity. Inhibition of mTOR by RAD001 enhances S184 Bax phosphorylation in lung cancer cell lines and tumor tissues from lung cancer patients treated with RAD001, which inactivates the propaoptotic function of Bax, contributing to rapalog-resistance. Combined CYD-2-11 and RAD001 treatment not only displays strong synergistic activity against lung cancer but also overcomes rapalog-resistance in vitro and in vivo. Therefore, a mechanism-driven combination of Bax agonist and mTOR inhibitor represents a highly attractive therapeutic strategy to improve lung cancer patient outcomes.
Citation Format: Rui Li, Chunyong Ding, Jun Zhang, Maohua Xie, Dongkyoo Park, Ye Ding, Guo Chen, Guojing Zhang, Melissa Gilbert-Ross, Wei Zhou, Adam Marcus, Shi-Yong Sun, Zhuo Chen, Gabriel Sica, Suresh Ramalingam, Andrew Magis, Haian Fu, Fadlo Khuri, Walter Curran, Taofeek Owonikoko, Dong Shin, Jia Zhou, Xingming Deng. Modulation of Bax and mTOR for cancer therapeutics [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 2333. doi:10.1158/1538-7445.AM2017-2333
Abstract 2336: Novel regulatory mechanisms for Bcl2-related Ovarian Killer (BOK) expression in breast cancer
Authors: Onyeagucha Benjamin Chidi , Subbarayalu Panneerdoss , Rajamanickam Subapriya , Abdelfattah Nourhan , Timilsina Santosh , Guzman Rosa M. , Zeballos Carla , Eedunuri Vijay , Bansal Sanjay , Bansal Hima , Mohammad Tabrez A. , Chen Yidong , Rao Manjeet K. 
Published: July 2017

Abstract
Deregulation of apoptosis is central to cancer progression and a major obstacle to effective treatment. The Bcl-2 gene family members play important roles in the regulation of apoptosis and are frequently altered in cancers. One such member is Bcl-2-related Ovarian Killer (BOK), which is a pro-apoptotic protein. Despite its critical role in apoptosis, the regulation of BOK expression is poorly understood in cancers. Here, we discovered that miR-296-5p, regulates BOK expression by binding to its 3’UTR in breast cancers. Furthermore, we show that depletion of BOK by either miR-296-5p or siRNA against BOK protected breast cancer cells from undergoing paclitaxel-induced apoptosis. Interestingly, miR-296-5p also regulates the expression of Mcl-1, which is an anti-apoptotic protein and is highly expressed in breast cancers. Our results reveal that Mcl-1 is important for suppression of BOK function as ectopic BOK expression induced Mcl-1, while silencing of BOK resulted in reduced Mcl-1 levels in breast cancer cells. In addition, we show that specific silencing of Mcl-1 reduced the long-term growth of breast cancer cells, whereas BOK inhibition didn’t have any effect on the growth of breast cancer cells. Surprisingly, silencing of both Mcl-1 and BOK rescued the effect of Mcl-1 silencing on breast cancer cell growth, suggesting that BOK is important for attenuating cell growth in the absence of Mcl-1, and also showing a tight feedback regulatory loop between BOK and Mcl-1 in breast cancer cells. Furthermore, we demonstrated that BOK protein level is regulated post-translationally by GSK3α and to some extent GSK3β as GSK3 inhibitor (CHIR99021) or silencing of GSK3 significantly increased BOK protein levels in breast cancer cells. Notably, we found that Mcl-1 interacts with GSK3α/β and silencing of Mcl-1 using siRNA significantly attenuated endogenous GSK3α/β levels in breast cancer cells. Taken together, our results suggest that fine tuning (either post-transcriptionally by miR-296-5p or post-translationally by GSK3) of the levels of pro-apoptotic protein BOK and anti-apoptotic protein Mcl-1 decide the fate of cancer cells to either undergo Apoptosis or proliferation.
Citation Format: Benjamin Chidi Onyeagucha, Panneerdoss Subbarayalu, Subapriya Rajamanickam, Nourhan Abdelfattah, Santosh Timilsina, Rosa M. Guzman, Carla Zeballos, Vijay Eedunuri, Sanjay Bansal, Hima Bansal, Tabrez A. Mohammad, Yidong Chen, Manjeet K. Rao. Novel regulatory mechanisms for Bcl2-related Ovarian Killer (BOK) expression in 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 2336. doi:10.1158/1538-7445.AM2017-2336