bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2152: Protein phosphatase Mg2+ and Mn2+ dependent 1F promotes smoking-induced breast cancer by inactivating phosphorylated p53-induced signals
Authors: Chen Li-Ching 
Published: July 2017

Abstract
Previously we demonstrated that the activation of α9-nicotinic acetylcholine receptor (α9-nAchR) signaling by smoking promotes breast cancer formation. To investigate the downstream signaling molecules involved in α9-nAChR-induced breast tumorigenesis, we used real-time polymerase chain reactions and Western blotting to assess expression of protein phosphatase Mg2+/Mn2+ dependent 1F (PPM1F), a Ser/Thr protein phosphatase, in human breast cancer samples (n=167). Additionally, stable PPM1F-knockdown and overexpressing cell lines were established to evaluate the function of PPM1F. The phosphatase activity of PPM1F in nicotine-treated cells was assessed through Western blotting, confocal microscopy, and fluorescence resonance energy transfer. Higher levels of PPM1F were detected in the breast cancer tissues of heavy smokers (n=7, 12.8-fold) greater than of non-smokers (n= 28, 6.3-fold) (**p=0.01). In vitro, nicotine induced PPM1F expression, whereas α9-nAChR knockdown reduced the protein expression of PPM1F. A series of biochemical experiments using nicotine-treated cells suggested that the dephosphorylation of p53 (Ser-20) and BAX (Ser-184) by PPM1F is a critical posttranslational modification, as observed in breast cancer patients who were heavy smokers. These observations indicate that PPM1F may be a mediator downstream of α9-nAChR that activates smoking-induced carcinogenic signals. Thus, PPM1F expression could be used for prognostic diagnosis or inhibited
for cancer prevention and therapy.
Citation Format: Li-Ching Chen. Protein phosphatase Mg2+ and Mn2+ dependent 1F promotes smoking-induced breast cancer by inactivating phosphorylated p53-induced signals [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 2152. doi:10.1158/1538-7445.AM2017-2152
Abstract 2156: NSC59984 induces mutant p53 degradation via activating ERK2 pathway-MDM2 axis
Authors: Zhang Shengliang , Zhou Lanlan , Dicker David , El-Deiry Wafik S. 
Published: July 2017

Abstract
Mutant p53 protein is highly expressed in most cancer cells due to its protein stabilization. Mutant p53 loses wild-type p53 function but gains new oncogenic functions in driving tumor growth and drug resistance. Depletion of mutant p53 is an attractive strategy for cancer therapy. We reported a small-molecule NSC59984 destabilizes mutant p53 protein via protein degradation (Zhang et al., Cancer Research, 2015). In this study, we demonstrate that the ERK2 pathway plays a specific role in NSC59984-induced mutant p53 degradation via MDM2-mediated ubiquitination. We observe a sustained-phosphorylation of ERK1/2 in cancer cells treated with NSC59984. ERK1/2 pathway is negatively regulated by MKP-1. We find that MKP-1 activity is partially inhibited by NSC59984 in a dose dependent manner in vitro. These results suggest that NSC5998 sustains ERK1/2 phosphorylation partially via disruption of the feedback-loop between MKP-1 and ERK2 pathway. Knockdown of ERK2 rescues mutant p53 from NSC59984-mediated degradation, and inhibits NSC59984-restoration of p53 signaling in mutant p53-expressing cells. On the contrary, the effect of NSC59984 on the mutant p53 is not inhibited by the blockage of JNK and P38, two pathways negatively regulated by MKP-1. These results suggest that the ERK2 phosphorylation is specifically required for NSC59984-mediated mutant p53 degradation. We further find that NSC59984 induces ERK2-dependent MDM2 phosphorylation. The effect of NSC59984 on MDM2 phosphoryation is partially inhibited by the blockage of ERK2 signaling (via U0126 treatment or Knockdown of ERK2), not by the attenuation of the JNK pathway. Furthermore, NSC59984-mediated mutant p53 protein degradation is inhibited by MDM2 knockdown, and enhanced by MDM2 overexpression in cancer cells. NSC59984-increased ubiquitination of mutant p53 is attenuated by U0126. Our results suggest that the ERK2 signaling pathway-MDM2 axis is a major determinant of NSC59984-mediated mutant p53 degradation. We further demonstrate that NSC59984 induces cell death via apoptosis, and NSC59984-induced cell death is mainly rescued by inhibition of the ERK2 pathway in p53 mutant cancer cells. Taken together, our results suggest that phosphorylated-ERK2 is an important factor required for NSC59984-mediated mutant p53 degradation which may further contribute to NSC59984-induced cell death in cancer cells.
Citation Format: Shengliang Zhang, Lanlan Zhou, David Dicker, Wafik S. El-Deiry. NSC59984 induces mutant p53 degradation via activating ERK2 pathway-MDM2 axis [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 2156. doi:10.1158/1538-7445.AM2017-2156
Abstract 2165: Deletion of survivin sensitize human hepatocellular carcinoma cells to low dose of doxorubicin and induce apoptosis
Authors: George Joseph , Hayashi Nobuhiko , Saito Takashi , Ozaki Kazuaki , Toshikuni Nobuyuki , Tsuchishima Mutsumi , Tsutsumi Mikihiro 
Published: July 2017

Abstract
Background and Aims: Hepatocellular carcinoma (HCC) is one of the most common cancers in the world and patients with advanced HCC face a dismal prognosis due to lack of effective therapy. Survivin, a member of the family of inhibitor of apoptosis proteins, is highly upregulated in HCC as well as in experimentally induced intrahepatic tumors. Doxorubicin, the only known chemotherapeutic agent for HCC, is cardiotoxic in addition to several well known side effects.
Methods: Survivin gene deletion was established in HepG2, Hep3B, and PLC/PRF/5 human HCC cells using CRISPR/Cas9 system. All the three HCC cells in culture were treated with doxorubicin at various concentrations before and after survivin gene knockout upto 72 hr. TUNEL assay and FACS analysis were performed to demonstrate the induction of apoptosis after doxorubicin treatment. Western blotting was carried out for cleaved fragments of caspase-9 and caspase-3 as well as major apoptotic executioner molecules.
Results: Cell viability studies depicted around 20% cell death at 24 h, 50% at 48 h, and 80% at 72 h after treatment with doxorubicin at 1 µM (final concentration in the media). Among the three cell lines studied, Hep3B cells were more susceptible to doxorubicin compared to HepG2 and PLC/PRF/5 cells. After deletion of survivin gene, the dosage of doxorubicin could reduce to five fold (200 nM, final concentration in the media) with the same cytotoxic effect before the knockout of survivin gene. HCC cells treated with reduced doses of doxorubicin depicted induction of apoptosis that was proved with TUNEL assay and FACS analysis as wells as increased levels of cleaved caspases and major apoptotic executioner molecules.
Conclusions: Our studies demonstrated that blocking of survivin molecule with effective methods would be a successful approach to treat primary hepatic tumors with low and safe doses of doxorubicin and other anticancer agents.
Note: This abstract was not presented at the meeting.
Citation Format: Joseph George, Nobuhiko Hayashi, Takashi Saito, Kazuaki Ozaki, Nobuyuki Toshikuni, Mutsumi Tsuchishima, Mikihiro Tsutsumi. Deletion of survivin sensitize human hepatocellular carcinoma cells to low dose of doxorubicin and induce 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 2165. doi:10.1158/1538-7445.AM2017-2165
Abstract 2168: Nucleic acid clamp-mediated recognition and transcriptional modulation of MYC oncogenes through the stabilization of G-quadruplexes
Authors: Hao Taisen , Brooks Tracy A. 
Published: July 2017

Abstract
G-quadruplexes (G4s) tend to cluster around biologically important regions such as promoters of DNA, 5’-UTR of mRNA and telomeres. Modulating the stability of G4 as in these regulatory sequences is an emerging approach for cancer treatment. MYC proto-oncogene is overexpressed in over 80% of tumor types, contributing to deregulated cancer cell proliferation. Silencing MYC expression has been demonstrated to be an effective approach to inhibit tumor growth. Among all the silencing strategies, stabilizing MYC promoter G4 that serves as an on-off switch for the transcription of MYC has been explored by the targeting of small molecules. However, the binding specificity of small molecule retarded the drug development process. Exploring novel MYC G4-targeting strategies is necessary to potentiate the pharmacological specificity of MYC G4 modulation. Here, we adopted a nucleic acid clamp based approach to recognize and stabilize the physiologically predominant MYC G4. Previously, a clamp (clamp A) was been demonstrated to recognize the physiologically relevant MYC G4 with high specificity and to downregulate MYC promoter activity. In the current research, we modified and optimized this clamp to allow for flexibility with labeling and monitoring techniques. The original 18 Å polyethylene glycol phosphate linker connecting the 5’ and 3’ regions of clamp A were substituted with thymine bases of varying lengths; 5 thymines were found to be optimal. The binding specificity and MYC G4 recognizing ability of this optimized clamp A T5 were confirmed by EMSA and ECD; the G4 stabilizing ability of clamp A T5 was demonstrated by DMS footprinting. The cytotoxicity of clamp A T5 was examined by MTS assay on HEK-293 and MCF-7 cells. The intracellular localization of clamp A T5 is being determined microscopically with a 6-FAM-labeled clamp A T5 after being transfected into and incubated with HEK-293 and MCF-7 cells for 48 hr. Nuclear localization is being examined by co-staining with DAPI, and MYC promoter localization is being determined by clustering with a MYC FISH probe. The modification of the clamp is both cost-effective, and enables the detailed study of intracellular functions. This clamp has potential as both a diagnostic tool to inform the use of MYC G4-targeted small molecules, and as a nanotherapeutic.
Citation Format: Taisen Hao, Tracy A. Brooks. Nucleic acid clamp-mediated recognition and transcriptional modulation of MYC oncogenes through the stabilization of G-quadruplexes [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 2168. doi:10.1158/1538-7445.AM2017-2168
Abstract 2171: Multi-CDK inhibition efficiently suppresses AR function and cell growth in prostate cancer
Authors: Simons Brian W. , Ybanez Maria , Antonarakis Emmanuel S. , Luo Jun , Nelkin Barry D. 
Published: July 2017

Abstract
Metastatic castration resistant prostate cancer (CRPC) continues to result in over 26,000 deaths per year in the United States. For 70 years, therapy for advanced prostate cancer has relied on AR-directed therapies. Unfortunately, even with the second generation androgen deprivation compounds, treated cancers commonly progress to castration resistance and lethality. This progression to castration resistance remains the central therapeutic roadblock for advanced prostate cancer. Importantly, in the vast majority of CRPC cases, the tumor still depends on AR signaling, but this signaling becomes androgen independent. The most common mechanisms, including mutation, protein truncation, and alternative splicing, affect the C-terminal domain, suggesting that antagonism of AR function via the N-terminal domain may be a promising target for CRPC therapy. Several groups have shown that CDKs 1, 5 and 9 activate AR by phosphorylation of the N-terminal domain. Here, we show that the multi-CDK inhibitor roniciclib (BAY1000394) inhibits activation of AR in a panel of prostate cancer cell lines, including several cell lines which exhibit androgen-independent AR signaling via AR-V7 alternative splicing. In vivo, roniciclib inhibited growth of prostate cancer xenografts. Since AR inhibition in prostate cancer has been shown to induce compensatory PI3K signaling, we also treated xenografts with a combination of roniciclib and the PI3K inhibitor copanlisib (BAY 80-6946). This combination was especially effective, and was well tolerated by the mice. Our results suggest that a combination of a multi-CDK inhibitor and a PI3K inhibitor may be promising for CRPC therapy.
Citation Format: Brian W. Simons, Maria Ybanez, Emmanuel S. Antonarakis, Jun Luo, Barry D. Nelkin. Multi-CDK inhibition efficiently suppresses AR function and cell growth in prostate 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 2171. doi:10.1158/1538-7445.AM2017-2171
Abstract 218: Functional proteomic analysis of TβRI immunocomplex in TGF-β signaling
Authors: Tang Liuya , Meng Zhaojing , Heller Mary , Zhou Ming , Zhang Ying 
Published: July 2017

Abstract
Transforming growth factor-beta (TGF-β) regulates a wide array of biological responses ranging from proliferation to apoptosis, and alterations in its signaling pathway are associated with a variety of human diseases, including cancer. During the activation of TGF-β signaling, TGF-β receptor I (TβRI) plays an important role in transducing signals to downstream effectors. To identify TβRI interacting proteins which are responsible for Smad-dependent pathways as well as Smad-independent pathways, we employed a large-scale quantitative proteomic analysis of TβRI immunocomplex. AML12 cells were labeled with L-Lysine and L-Arginine (K0R0, light) or L-Lysine-13C6-15N2 and L-Arginine-U-13C6-15N4 (K8R10, heavy). The cells cultured in K8R10 medium (H: Heavy) were transfected with Flag-TβRI, while the cells cultured in K0R0 medium (L: Light) were transfected with Flag vector. The cell lysates were combined at equal protein amount, and TβRI immunocomplex were purified using FLAG M2 agarose. The resulting peptides from eluted TβRI immunocomplex were subjected to mass spectrometry quantitation. If a protein whose ratio of H/L was not smaller than 1.3, it was categorized as a constitutively interacting protein of TβRI. A total of 687 proteins were quantitated and 325 proteins were defined as constitutively interacting proteins. Pathway enrichment analysis found these proteins are involved in a number of signaling pathways, which indicates the cross-talks between TGF-β signaling and other signaling. Future work will include validation of interaction between TβRI and candidate proteins, and understand functional significance of candidate proteins in TGF-β signaling or signaling cross-talks by a series of molecular biological approaches.
Citation Format: Liuya Tang, Zhaojing Meng, Mary Heller, Ming Zhou, Ying Zhang. Functional proteomic analysis of TβRI immunocomplex in TGF-β signaling [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 218. doi:10.1158/1538-7445.AM2017-218
Abstract 2191: Multiple imaging reporter labeled acid-degradable dextran nanopolymer as a COX-2 siRNA carrier for COX-2 specific downregulation
Authors: Chen Zhihang , Krishnamachary Balaji , Penet Marie-France , Bhujwalla Zaver M. 
Published: July 2017

Abstract
Cyclooxygenase-2 (COX-2) as a target has attracted interest for multiple degenerative diseases and cancers. COX-2 siRNA provides specific and effective down-regulation of COX-2. However, because artificial cationic polymers can induce proinflammatory signals that increase COX-2 expression, there are few if any reports about the use of artificial cationic polymers as siRNA carrier to downregulate COX-2 in cancer cells. Here we developed a method to efficiently synthesize a multiple imaging reporter labeled biodegradable dextran to use as an efficient cationic polymer carrier for COX-2 siRNA delivery. Amine function groups were conjugated to the dextran platform through acetal bonds. Acetal bonds were broken at acidic conditions that occur in cancer and endocytosis compartments. Rhodamine was labeled to the amine groups to detect degradation and removal of these groups from the cell, while the dextran scaffold was labeled with Cy5.5. The rapid cleavage and release of amine groups minimized the proinflammatory side effects of the positively charged amine groups.Colorimetric assay of Cy5.5 and rhodamine in different pH buffer indicated that the amine group was cleaved at pH 5.5 buffer but was stable in pH 7.4 buffer. Fluorescence imaging showed that the dextran siRNA nanoplex entered the cells through endocytosis that provided acidic conditions for the breaking of the amine group. For the first time, the intracellular breaking of acetal bonds was clearly visualized by multiple imaging reporters. Because the rapid cleavage and release of amine groups minimized the proinflammatory side-effects, quantitative reverse transcription polymerase chain reaction (qRT-PCR) assay indicated that this dextran COX-2 siRNA nanoplex could downregulate COX-2 expression efficiently. Prostaglandin E2 level decreased significantly with COX-2 siRNA/dextran treatment. In vivo imaging demonstrated that the COX-2 siRNA/dextran nanoplex accumulated in MDA-MB-231 tumors. QRT-PCR and western blot assays of COX-2 levels in tumor tissue demonstrated that this nanoplex significantly downregulated COX-2 expression in vivo efficiently and within 24h. This dextran nanopolymer can be used as a safe, reproducible, and biocompatible siRNA carrier to effectively reduce COX-2 expression in cancer cells and tumors.
Citation Format: Zhihang Chen, Balaji Krishnamachary, Marie-France Penet, Zaver M. Bhujwalla. Multiple imaging reporter labeled acid-degradable dextran nanopolymer as a COX-2 siRNA carrier for COX-2 specific downregulation [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 2191. doi:10.1158/1538-7445.AM2017-2191
Abstract 22: MM-161, a first-in-class pan-FGFR antibody
Authors: Dake Tamara , Finn Greg , Geddie Melissa , Kohli Neeraj , Razlog Maja , Xu Lihui , Paragas Violette , Yuzugullu Haluk , Ghassemifar Sara , Hashambhoy-Ramsay Yasmin , McDonagh Charlotte , Muda Marco , Schoeberl Birgit 
Published: July 2017

Abstract
Aberrant signaling of the FGFR pathway has long been known to promote tumorigenesis and angiogenesis across multiple cancer indications. However, the development of an effective and well-tolerated FGFR targeted inhibitor has been hindered by the need to block the activation of multiple mitogenic receptors while avoiding significant toxicities associated with blocking endocrine FGF ligands.
Here we disclose for the first time a novel FGFR targeted antibody, MM-161, designed to block ligand-dependent signaling driven by all four FGF receptors, specifically the IIIc-isoforms. MM-161 is well tolerated in mice and cynomolgus monkeys with no significant weight loss observed in either species. Efficacy studies demonstrated that MM-161 monotherapy leads to significant tumor growth inhibition or tumor regression of xenografts of human lung, renal and endometrial cancer amongst others. Importantly, MM-161 has a dual mechanism of action by inhibiting both proliferation and angiogenesis. We will present data illustrating that inhibition of multiple FGFRs is desirable to achieve tumor regression. Furthermore, we will show combination studies with relevant standard of care therapies in models of lung and renal cancer.
Taken together, our preclinical data strongly supports the clinical evaluation of MM-161 in cancer patients.
Citation Format: Tamara Dake, Greg Finn, Melissa Geddie, Neeraj Kohli, Maja Razlog, Lihui Xu, Violette Paragas, Haluk Yuzugullu, Sara Ghassemifar, Yasmin Hashambhoy-Ramsay, Charlotte McDonagh, Marco Muda, Birgit Schoeberl. MM-161, a first-in-class pan-FGFR antibody [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 22. doi:10.1158/1538-7445.AM2017-22
Abstract 220: Proteomic identification of therapeutics targets for Enzalutamide resistance in Castration Resistant Prostate Cancer
Authors: VELOT Lauriane , Levesque Dominique , Boisvert François-Michel , Bisson Nicolas , Pouliot Frédéric 
Published: July 2017

Abstract
Prostate cancer (PC) is the most frequently diagnosed cancer in Canadian men and is the 3rd cause of cancer mortality. The Androgen Receptor (AR) is activated by androgens (e.g. testosterone), which leads to prostatic cell proliferation. The primary treatment for advanced PC is androgen-deprivation therapy, which is achieved via surgical or chemical castration. Nevertheless, most PC will become castration-resistant (CRPC). Although new anti-androgens (e.g. Enzalutamide) were developed to improve patients’ survival, their efficacy is still very limited and most CRPC patients will die from the disease within a few years. We postulate that by gaining insights into AR signalling networks in the context of CRPC, we could better direct patients towards the best-suited therapy and propose new therapeutic targets.
To this aim, we took advantage of an innovative proteomics approach, namely proximity-labeling (BioID), to characterize global AR signalling networks in hormone-dependant LAPC4 cells. We identified 45 AR-associated proteins in non-stimulated cells, 35 of which were not previously reported. Upon androgenic stimulation, the AR signalling network increased to 320 proteins, including 278 (253 were novel) that were restricted to androgen-stimulated cells. Enzalutamide treatment resulted in a loss of 259 proteins from the network when compared to stimulated cells. As expected, this reproduced quite faithfully the status of non-stimulated LAPC4 cells. Interestingly, we identified 4 proteins in the AR network specifically after Enzalutamide treatment. These are interesting targets that may be relevant for the acquisition or the prediction of Enzalutamide resistance. Hence, they could become in time alternative therapeutic targets for CRPC treatment, to be used when Enzalutamide fails.
Citation Format: Lauriane VELOT, Dominique Levesque, François-Michel Boisvert, Nicolas Bisson, Frédéric Pouliot. Proteomic identification of therapeutics targets for Enzalutamide resistance in Castration Resistant Prostate 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 220. doi:10.1158/1538-7445.AM2017-220