bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3520: Solidago virga-aurea extract induced apoptosis of breast cancer cells through FOXO3 mediated bim expression
Authors: Kim Haesung , Kim Chea Ha , Kim Jeong-Hyeon , Lee Jeong-Min , Jeon Jeong-Ho , Lee Jae-Yong 
Published: July 2016

Abstract
Solidago virga-aurea (European goldenrod or woundwort) is an herbaceous perennial plant of the family Asteraceae. It is used for medical system with astringent, diuretic, antiseptic and homeopathic properties. And the studies about Solidago virga-aurea are in progress for the other functions.
Recently, we found that Solidago virga-aurea extract induces apoptosis of breast cancer cells. MTT assay showed that cellular viability was decreased in Solidago virga-aurea extract treated MDA-MB-231 and MCF-7 breast cancer cell lines by dose and time dependent manner. And apoptotic protein, especially bim, was increased in Solidago virga-aurea extract treated MCF-7 cell line. However, anti-apoptotic protein, Bcl-xL, does not changed by Solidago virga-aurea extract. In order to find out positive regulator of bim expression, we tested whether FOXO (forkhead-box transcription factor, group O) 3a and AMPK (5’ AMP-activated protein kinase) protein expression. In immunoblot analysis showed that FOXO3a expression level was dramatically increased in Solidago virga-aurea treated MCF-7 cells without changes of AMPK expression. Moreover, immunostaining showed that Solidago virga-aurea induces co-localization of FOXO3a and bim proteins in MCF-7 and MB-231 cells.
Taken together, Solidago virga-aurea induces apoptosis by FOXO3a mediated up-regulation of bim protein. The mechanisms of Solidago virga-aurea mediated FOXO3a regulation is not fully elucidated yet, but further studies about this molecular mechanism between two proteins will give some ideas for cancer therapies for certain breast cancer patients.
Citation Format: Haesung Kim, Chea Ha Kim, Jeong-Hyeon Kim, Jeong-Min Lee, Jeong-Ho Jeon, Jae-Yong Lee. Solidago virga-aurea extract induced apoptosis of breast cancer cells through FOXO3 mediated bim expression. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3520.
Abstract 3522: Cyclins and CDKs regulation and caspase cascade activation by cucurbitacin D induced cell cycle arrest and apoptosis in pancreatic tumor
Authors: Kim Myeong-Sun , Kim Ji Hye , Ku Jin Mo , Hong Se Hyang , Lee Kangwook , Choi Hyeong Sim , Woo Sang Mi , Chang Jee Yun , Kim Tai Young , Ko. Seong Gyu Ko 
Published: July 2016

Abstract
Pancreatic cancer has a poor prognosis and very low survival rate over the world. Because pancreatic cancer probably is diagnosed at a late stage, aggressive local invasion, and poor response to chemotherapy. Gemcitabine was the standard treatment for advanced and metastatic pancreatic cancer patients, but it is associated with multiple adverse effects-fever, fatigue, nausea, and drug resistance. Whether cucurbitacin D has any efficacy against human pancreatic cancer was examined in cell culture system. In vitro, cell viability was measured by MTT assay to recognize of cell cytotoxicity. Consequently, cytotoxicity was observed at a low concentration of cucurbitacin D. Wound healing assay and clonogenic assay indicated that cucurubitacin D inhibited the growth of cell growth through cyclins and CDKs regulation, and decreased colony-forming ability. Also, this compound down-regulated expression level of anti-apoptotic protein, Bcl-2, up-regulated of pro-apoptotic molecule Bax, and activated caspase-8, caspase-3 cascade extrinsic pathway. Additionally, PARP, caspase-3 substrate, protein was cleaved by cucurbitacin D treatment. Overall, our study suggest that cucurbitacin D could be a clinical medicine for the treatment of pancreatic cancers.
Citation Format: Myeong-Sun Kim, Ji Hye Kim, Jin Mo Ku, Se Hyang Hong, Kangwook Lee, Hyeong Sim Choi, Sang Mi Woo, Jee Yun Chang, Tai Young Kim, Seong Gyu Ko Ko. Cyclins and CDKs regulation and caspase cascade activation by cucurbitacin D induced cell cycle arrest and apoptosis in pancreatic tumor. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3522.
Abstract 3533: Role of autophagy-related protein expression in patients with rectal cancer treated with neoadjuvant chemoradiotherapy
Authors: Ko Yoon Ho , Hong Soon Uk , Sun Der Sheng , Won Hye Sung , Lee Myung Ah , Shim Byoung Young 
Published: July 2016

Abstract
Background: Autophagy, a cellular degradation process, has complex roles in tumourigenesis and resistance to cancer treatment in humans. The aim of this study was to explore the expression levels of autophagy-related proteins in patients with rectal cancer and evaluate their clinical role in the neoadjuvant chemoradiotherapy setting.
Methods: All specimens evaluated were obtained from 101 patients with colorectal cancer who had undergone neoadjuvant chemoradiotherapy and curative surgery. The primary outcomes measured were the expression levels of two autophagy-related proteins (microtubule-associated protein 1 light chain 3 beta (LC3β) and beclin-1) by immunohistochemistry and their association with clinicopathological parameters and patient survival.
Results: Among the 101 patients, the frequency of high expression of beclin-1 was 31.7% (32/101) and that of LC3β was 46.5% (47/101). A pathologic complete response was inversely associated with LC3β expression (P = 0.003) and alterations in the expression of autophagy-related proteins (P = 0.046). In the multivariate analysis, however, autophagy-related protein expression did not show prognostic significance for relapse-free survival or overall survival.
Conclusions: High expression of autophagy-related proteins shows a strong negative association with the efficacy of neoadjuvant chemoradiotherapy in patients with rectal cancer. Autophagy has clear implications as a therapeutic target with which to improve the efficacy of neoadjuvant chemoradiotherapy.
Citation Format: Yoon Ho Ko, Soon Uk Hong, Der Sheng Sun, Hye Sung Won, Myung Ah Lee, Byoung Young Shim. Role of autophagy-related protein expression in patients with rectal cancer treated with neoadjuvant chemoradiotherapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3533.
Abstract 3538: Effects of oral chloroquine administration on a preclinical mouse model of PTEN/p53-deficient prostate cancer
Authors: De Velasco Marco A. , Sugimoto Koichi , Kura Yurie , Hatanaka Yuji , Yamamoto Yutaka , Oki Takashi , Yoshimura Kazuhiro , Nozawa Masahiro , Yoshikawa Kazuhiro , Nishio Kazuto , Uemura Hirotsugu 
Published: July 2016

Abstract
Autophagy is cellular process that can promote tumor survival during periods of metabolic and therapeutic stress. Inhibition of autophagy can promote senescence resulting in decreased tumor growth. Genetic alterations of PTEN and p53 are frequently present in advanced human prostate cancer and are associated with poor prognosis. In mouse models, the inactivation of PTEN leads to the development of prostate tumors that progress slowly, in part due to the induction of PTEN-(loss)-induced cellular senescence. Concomitant inactivation of both PTEN and P53 in prostate leads to the development of an aggressive cancer phenotype that can overcome PTEN-(loss)-induced cellular senescence and is characterized with accelerated growth, metastatic development and decreased survival. Published findings show that in some cancer models, the effects of autophagy inhibition are dependent on p53 status. In this study we assessed the effects of pharmacological inhibition of autophagy with chloroquine (CQ) on the growth and progression of mouse prostate tumors driven by the concomitant inactivation of PTEN and p53. CQ is a lysosomotropic agent that has widely used to impede autophagy and inhibit the growth of human tumor cells in vitro and in vivo. Genetically engineered mice with the conditional inactivation of PTEN and p53 were used to evaluate the antitumor effects and therapeutic benefit of CQ in a drug intervention model of prostate cancer. Twenty-seven-week-old PTEN/p53 double knockout mice bearing prostate tumors were randomized to control and oral CQ (100 mg/kg in drinking water) treatment groups. Progression-free survival was 145 days versus 161 days (P = 0.703) for control and CQ treated mice, respectively. Median overall survival was 170 days versus 147 days (P = 0.523) for control and CQ treated mice, respectively. Tumor burden assed by the median genitourinary tract weight was 2.42 grams versus 2.19 grams (P = 0.645) for control and CQ treated mice, respectively. Our molecular assays revealed that CQ failed to consistently inhibit autophagy in tumors at the present dose. Overall, our findings show that CQ alone did not provide treatment benefit in mouse prostate cancer with loss of p53.
Citation Format: Marco A. De Velasco, Koichi Sugimoto, Yurie Kura, Yuji Hatanaka, Yutaka Yamamoto, Takashi Oki, Kazuhiro Yoshimura, Masahiro Nozawa, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura. Effects of oral chloroquine administration on a preclinical mouse model of PTEN/p53-deficient prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3538.
Abstract 3539: Vitamin D/EB 1089 mediated radio-sensitization of lung cancer cells and head and neck cancer cells
Authors: Thekkudan Theresa , Sharma Khushboo , Saleh Tareq , Gewirtz David 
Published: July 2016

Abstract
Lung cancer is a principal factor contributing to cancer-related mortality in the United States. Patients with lung cancer generally have a poor prognosis and resection is often not possible. Our previous work has demonstrated that Vitamin D and its analog, EB1089 (EB), enhance radio sensitivity of H460 and A549 non-small cell lung cancer (NSCLC) cells (Sharma et al; A novel cytostatic form of autophagy in sensitization of non-small cell lung cancer cells to radiation by vitamin D and the vitamin D analog, EB 1089. Autophagy; 2014;10(12):2346-61). In this study, we have extended these findings of Vitamin D/EB 1089 induced radio-sensitization in multiple tumor cell lines such as Lewis Lung mouse non-small cell lung cancer cells (LLC), head and neck cancer cells (HN30) and a primary cell line established from a lung tumor obtained from a cancer patient.
All cell lines were treated with multiple doses of radiation in the range of 2-6 Gy and EB1089 was used at concentration of 100nM. Sensitivity was determined based on viable cell number and clonogenic survival.
We observed enhanced radiation sensitivity of LLC and HN30 cells with the combination treatment of radiation and EB1089. However, as reported previously by our laboratory (Sharma et al., 2014; Autophagy), sensitization was dependent on the presence of functional p53 and was not evident in HN6 head and neck tumor cells that are mutant in p53. These data suggest that Vitamin D or a Vitamin D analog could be used to enhance radiation sensitivity of various malignancies but only where the tumors express wild type p53. Furthermore, we were able to demonstrate sensitization in a primary cell line established from lung tumor tissues utilizing conditioned medium from stromal cells treated with EB1089. These data suggest that stromal re-programming of cancer cells could influence radiation sensitivity.
In studies to define the signaling pathways associated with radiation sensitization, we also observed inactivation by EB 1089 of the NF-kB pathway that was activated by radiation alone in H460 and H1299 NSCLC cells. Silencing of AMPK attenuated radiation sensitization by EB 1089. Sensitization was accompanied by enhanced secretion of the autophagy/senescence related marker, HMGB1. Taken together, these studies indicate that Vitamin and/or its analogs enhance radiosensitivity by cellular pathways involving NF-kB and AMPK and that HMGB1 may be secreted to activate an immune response to the combination treatment.
Citation Format: Theresa Thekkudan, Khushboo Sharma, Tareq Saleh, David Gewirtz. Vitamin D/EB 1089 mediated radio-sensitization of lung cancer cells and head and neck cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3539.
Abstract 3547: CEBPD induces apoptosis through autophagy in metformin-treated HCC
Authors: Lin. I P. 
Published: July 2016

Abstract
The patients with hepatocellular carcinoma (HCC) face the risk of cancer relapse or liver dysfunction. Metformin (Met), a first-line drug of type 2 diabetes, has been proved that it could induce G1 arrest and prevent or inhibit HCC. Previously, we demonstrated that the transcription factor CCAAT/enhancer-binding protein delta (CEBPD) plays a tumor suppressor and is responsive to many anticancer drugs in HCC. In this study, we found that Met could induce autophagy, growth arrest and further apoptosis in Huh7 cells. Met enhanced CEBPD expression via stabilizing its protein stability. The loss of CEBPD attenuated the Met-induced autophagy, growth arrest and apoptosis. Importantly, in addition to increasing P27 and down-regulating cyclin D1, CEBPD also contributed the increases of LC3B and ATG3 and LC3 puncta formation. We revealed a novel involvement of CEBPD in Met-induced growth arrest, apoptosis and autophagy of liver cancer cells through regulating p27, cyclinD1, LC3B and ATG3.
Citation Format: I P. Lin. CEBPD induces apoptosis through autophagy in metformin-treated HCC. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3547.
Abstract 3548: In vivo CRISPR reveals dual activation of apoptosis and necroptosis as means to eradicate drug resistant leukemia
Authors: Aguadé-Gorgorió Júlia , McComb Scott , Cario Gunnar , Stanulla Martin , Eckert Cornelia , Bourquin Jean-Pierre , Bornhauser Beat C. 
Published: July 2016

Abstract
Dysregulation of apoptosis constitutes a general mechanism for refractory acute lymphoblastic leukemia (ALL) to escape cell death during chemotherapy. We have assessed the potential of SMAC mimetic compounds (SM) to eradicate drug resistant ALL by blocking the pro-survival cellular inhibitor of apoptosis proteins (cIAPs). On the basis of a large xenograft bank of primary ALL samples, obtained by xenotransplantation in immunodeficient NSG mice, we detected exquisite sensitivity to SM in vitro in a third of the cases tested, including drug-resistant and relapsed samples. Potent in vitro activity was highly predictive of in vivo efficacy in the xenograft model. Treatment of transplanted mice with SM not only delayed leukemia progression, but also completely eliminated leukemia burden in established disease for several weeks following treatment. SM activity required the presence of RIP1, since lentiCRISPR mediated gene knockout of RIP1 in patient-derived ALL cells blocked SM-induced cell death in vivo and in vitro. In contrast, RIP1 loss had no significant impact on the response to standard antileukemic therapies, supporting a view that RIP1-dependent death pathways are not likely to be selected against by front line chemotherapy. Furthermore, using a multicolor lentiCRISPR approach for simultaneous disruption of multiple genes, we found that downstream of RIP1, the response to SM was dependent on simultaneous execution of apoptosis and necroptosis, since genetic targeting of both cell death pathways was required to block SM-induced death. Upstream of RIP1, expression levels of TNF receptor II (TNFR2) in primary ALL correlated with sensitivity to SM, and genetic disruption of TNFR2 conferred resistance to SM treatment in vivo. Thus, SM treatment circumvents drug resistance through parallel activation of RIP1-dependent apoptosis and necroptosis, providing a strong rationale for application in salvage treatment of refractory childhood ALL.
Citation Format: Júlia Aguadé-Gorgorió, Scott McComb, Gunnar Cario, Martin Stanulla, Cornelia Eckert, Jean-Pierre Bourquin, Beat C. Bornhauser. In vivo CRISPR reveals dual activation of apoptosis and necroptosis as means to eradicate drug resistant leukemia. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3548.
Abstract 3558: Predicting response to Mcl-1 targeting agents in NSCLC and multiple myeloma
Authors: McEachern Kristen , O’Connor Greg , Cidado Justin , Belmonte Matthew , Barry Evan , Dry Hannah , Secrist Paul , Drew Lisa 
Published: July 2016

Abstract
Mcl-1 is an anti-apoptotic member of the Bcl-2 family of proteins and is frequently amplified or over-expressed in both solid tumors and hematological malignancies, suggesting that its activity may be important for the survival of cancer cells. CDK9 inhibition results in the down regulation of Mcl-1 mRNA and subsequent protein levels by inhibiting transcription and represents an indirect approach to targeting Mcl-1. Mcl-1 can also be targeted directly using an inhibitor that disrupts the Mcl-1 complexes to induce apoptosis.
Using both molecular and pharmacological approaches, we sought to identify predictive biomarkers of Mcl1 dependency in sensitive NSCLC and multiple myeloma cell lines. Here we demonstrate that NSCLC cell lines lacking MCL1 gene copy number gains are not sensitive to siRNA mediated knockdown of Mcl-1 or Mcl-1 inhibition (cell line sensitivity to CDK9 or Mcl-1 inhibition is defined by potency and extent of caspase activation). However, the presence of a copy number alteration does not predict sensitivity to Mcl-1 inhibition. To better understand what the drivers of sensitivity are, we developed quantitative assays on the Peggy platform (a capillary based immunoassay platform by Protein Simple) to measure both Mcl-1 and Bcl-xL protein levels. Using these assays, we show a correlation between sensitivity to a CDK9 or Mcl1 inhibitor and Mcl-1 levels, as well as to the ratio of Mcl-1 to Bcl-xL protein in a NSCLC cell line panel.
These findings were then extended into a panel of multiple myeloma cell lines. While somewhat broad activity for CDK9 or Mcl-1 inhibition is seen across the cell lines tested, a subset of the sensitive lines have MCL1 amplification and express high levels of Mcl-1 protein. Mcl-1 levels alone, however, do not predict for sensitivity across the panel and, similar to NSCLC, the ratio of Mcl1 to Bcl-xL expression has greater positive predictive value.
These results provide the rationale for exploring Mcl-1 copy number alterations and Mcl-1 and Bcl-xL protein levels as predictive biomarkers for tumor response when treating with a CDK9 or Mcl-1 inhibitor in both NSCLC and multiple myeloma.
Citation Format: Kristen McEachern, Greg O’Connor, Justin Cidado, Matthew Belmonte, Evan Barry, Hannah Dry, Paul Secrist, Lisa Drew. Predicting response to Mcl-1 targeting agents in NSCLC and multiple myeloma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3558.
Abstract 3566: Glycosylation of the TNFR1 death receptor controls cell fate
Authors: Holdbrooks Andrew , Schultz Matthew J. , Liu Zhongyu , Bullard Daniel , Bellis Susan L. 
Published: July 2016

Abstract
Activation of the TNFR1 death receptor by TNFα can induce cell survival or cell death signaling, however, the mechanisms regulating this TNFR1 signaling switch are poorly understood. TNFα-induced apoptosis is reported to require higher-order clustering and internalization of activated TNFR1, whereas surface retention of the activated receptor has been shown to promote survival signaling mediated by NFκB and MAPKs. Studies from our group have identified a novel glycosylation-dependent mechanism that controls this signaling switch. Specifically, we have found that TNFR1 localization and activity are regulated by the addition of a distinct sugar, an α2-6 linked sialic acid, by the enzyme ST6Gal-I, a Golgi sialyltransferase whose expression is upregulated in many cancer types. The sialylation effect on TNFR1 was examined in epithelial and monocytic cancer cell lines with forced overexpression or knockdown of ST6Gal-I, as well as in primary monocytes obtained from mice with ST6Gal-I knock-in or knockout. Data from these models indicate that α2-6 sialylation of TNFR1 blocks TNFα-induced apoptosis, and the suggested mechanism underlying this inhibition of apoptosis is the sialylation-driven inhibition of TNFR1 oligomerization and internalization, as observed through immunoblotting, immunocytochemistry and flow cytometry. Considering sialylated TNFR1 is retained on the plasma membrane following activation, we hypothesize that ST6Gal-I functions to not only block TNFR1-mediated cell death but also divert the cell's activity to favor survival. Supporting this hypothesis, cells with elevated levels of ST6Gal-I exhibit heightened expression and activation of many pro-survival factors, such as NFκB, MAPKs and AKT, in addition to decreased activation of caspase-3. Since levels of ST6Gal-I are elevated in multiple tumor cell populations, our group proposes that ST6Gal-I protects tumor cells against TNFα-induced apoptosis within the inflammatory tumor microenvironment. As preliminary support for this concept, peritoneal ascites fluid was collected from ovarian cancer (OC) patients, and the acellular, cytokine-rich fraction was incubated with OC cell lines with or without forced ST6Gal-I expression. Expression of ST6Gal-I conferred strong protection against cell death induced by soluble ascites. Based on these collective findings, we postulate that sialylation of TNFR1 by ST6Gal-I diverts the cellular response to TNFα from apoptosis to survival, providing a mechanism by which tumor cells can evade immune cell killing.
Citation Format: Andrew Holdbrooks, Matthew J. Schultz, Zhongyu Liu, Daniel Bullard, Susan L. Bellis. Glycosylation of the TNFR1 death receptor controls cell fate. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3566.