bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 544: Characterization of serine/threonine kinase LASK2 as a biomarker and therapeutic target for lung cancer
Authors: Daigo Yataro , Takano Atsushi , Nakamura Yusuke 
Published: August 2018

Abstract
As the number of lung cancer patients responding well to standard therapies is still small, further development of new anti-cancer drugs with minimum risk of adverse event and highly sensitive cancer biomarkers is urgently awaited. We have been developing new molecular therapies targeting oncoproteins with their companion biomarkers by screening system as follows; i) To identify up-regulated genes in 120 lung cancers by the gene expression microarray representing 27,648 genes, ii) To verify the candidate genes for their low expression in 23 normal tissues, iii) To validate the clinicopathological significance of their protein expression by tissue microarray covering hundreds of non-small cell lung cancers (NSCLCs), iv) To verify whether they are essential for the growth/invasion of cancer cells by siRNAs. During this process, we selected dozens of druggable oncoproteins with various enzymatic activities, and identified activation of serine/threonine kinase LASK2 (lung cancer-associated kinase 2) in the majority of various histological types of lung cancers, but not in normal tissues except testis. Immunohistochemical analysis showed that strong LASK2 positivity was an independent prognostic factor for patients with NSCLC (P&lt;0.0001). Suppression of LASK2 expression with its siRNAs inhibited growth of lung cancer cells. The enhanced cellular proliferation by introduction of LASK2 in mammalian cells also supported its oncogenic function in vitro and in mice model. Induction of LASK2 appeared to increase the levels of phosphorylation of oncogenic signal proteins for lung cancer such as MAPK. The data suggest that LASK2 is a candidate prognostic biomarker and possible therapeutic target for lung cancers.
Citation Format: Yataro Daigo, Atsushi Takano, Yusuke Nakamura. Characterization of serine/threonine kinase LASK2 as a biomarker and therapeutic target for lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 544.
Abstract 5440: Role of tyrosine phosphorylation of β-catenin in EGFR-mutant lung cancer
Authors: Fujii Masanori , Nakayama Sohei , Shimizu Kohei , Takei Hisashi , Ando Mariko , Heo Eunyoung , Kobayashi ikei , Pan Gilbert , Inuzuka Hiroyuki , Kobayashi Susumu 
Published: August 2018

Abstract
Wnt/ β-catenin signaling plays a key role in the pathogenesis of colon and other cancers. Emerging evidence indicates that oncogenic β-catenin regulates several biological processes essential for cancer initiation and progression. The role of β-catenin in lung cancer with epidermal growth factor receptor (EGFR) activating mutations has not been fully understood; however, recent studies suggest that co-occurring genetic alterations in CTNNB1 might cooperate with mutant EGFR in promoting tumor progression and treatment resistance to EGFR-tyrosine kinase inhibitors (EGFR-TKIs). This sheds new light on this pathway in EGFR-mutant lung cancer. We previously demonstrated that β-catenin plays an essential role in lung tumorigenesis driven by EGFR mutants, particularly EGFR-T790M. We also found that β-catenin is activated through tyrosine-phosphorylation by EGFR mutants. In this study, we identified five tyrosine phosphorylation sites (Y5) of β-catenin by mass spectrometry. Tyrosine phosphorylation at these sites may be critical in β-catenin stability, nuclear translocation and its role as a transcriptional switch in oncogenesis. Firstly, we demonstrated that tyrosine phosphorylation of β-catenin disrupts the binding of a main ubiquitin ligase β-Trcp1, leading to an escape from degradation. Secondly, in contrast to known transcriptional activity with TCF/LEF, β-catenin that is tyrosine phosphorylated by mutant EGFR was found to form a complex with a transcriptional regulator, YAP1, and a transcriptional factor, TBX5. Immunoprecipitation experiments suggested Y5 tyrosine phosphorylation of β-catenin plays a critical role in the interaction between β-catenin and TBX5. Moreover, this complex may regulate anti-apoptotic genes, including BCL2L1, which encodes Bcl-xL. Combination treatment with osimertinib, a 3rd generation EGFR-TKI, and dasatinib suppressed Y5 tyrosine phosphorylation of β-catenin, leading to reduced Bcl-xL expression. Subsequent TBX5 knockdown in vitro decreased Bcl-xL expression while Bcl2l1 knockout in vivo mouse models suppressed lung tumor development. These observations suggest that β-catenin-YAP1-TBX5 complex contributes to EGFR-T790M lung cancer and may serve to explain the underlying mechanism for EGFR-TKIs resistance and for the effectiveness of combination therapy with osimertinib and dasatinib.
Citation Format: Masanori Fujii, Sohei Nakayama, Kohei Shimizu, Hisashi Takei, Mariko Ando, Eunyoung Heo, ikei Kobayashi, Gilbert Pan, Hiroyuki Inuzuka, Susumu Kobayashi. Role of tyrosine phosphorylation of β-catenin in EGFR-mutant lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5440.
Abstract 5441: Regulation of AKT phosphorylation by GSK3β and PTEN to control chemoresistance in breast cancer
Authors: Gao Chunyi , Wang Guohua , Jiang Zhenglin 
Published: August 2018

Abstract
Background Chemotherapy is an important element in the treatment paradigm for breast cancers. However, the resistance of cancer cells to chemotherapeutic agents frequently results in the subsequent recurrence and metastasis. AKT phosphorylation is highly expressed or over-expressed in chemoresistant tumor samples. However, the precise molecular mechanism involved in AKT phosphorylation-related chemoresistance in breast cancer remains unknown. The aim of the present study was to assess whether the role of AKT phosphorylation in the cell viability and chemoresistance of breast cancer. Methodology/Principal Findings We developed two taxol resisted breast cancer cells: TAX Resis HepG2 and TAX Resis HepG2 SMMC7721. Western blot and immunofluorescence analysis indicated that glycogen synthase kinase 3 beta (GSK3β), phosphorylated phosphatase and tension homologue (p-PTEN) and phosphorylation of AKT (p-AKT) were highly expressed in taxol resisted HepG2 and SMMC7721 cells. The increase of GSK3β phosphorylated and inactivated PTEN, thereby enhanced phosphatidylinositide 3-kinases (PI3K)/Akt signaling. The increase in GSK3β, p-PTEN and p-AKT was associated with cell viability by MTT assay. Annexin-V-PI assay and transwell analysis were indicated that GSK3β knockdown with lentiviral shRNA (shRNA-GSK3β) promoted the apoptosis and suppressed the migration ability of Taxol resisted HepG2 and SMMC7721 cells, and both effects were reversed by activating p-AKT via PTEN inhibitor bpV(pic). Conclusions In conclusion, AKT phosphorylation manipulated by GSK3β and PTEN were correlated with cell viability, migration and apoptosis in Taxol resisted HepG2 and SMMC7721 cells, which may promote chemoresistance of breast cancer. Furthermore, functions of GSK3β can modulate cell viability via the PTEN/PI3K/Akt signaling pathway and induce chemoresistance, serving as a valuable molecular target for treatment of breast cancer.
Citation Format: Chunyi Gao, Guohua Wang, Zhenglin Jiang. Regulation of AKT phosphorylation by GSK3β and PTEN to control chemoresistance in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5441.
Abstract 5445: A novel mechanism of inhibition of ovarian cancer growth by Compound C, dorsomorphin
Authors: Ghoneum Alia , Afify Hesham M. , Said Neveen 
Published: August 2018

Abstract
High grade serous ovarian carcinoma (HGSC) is the most lethal gynecologic malignancy with a five-year survival rate of 15%. As a highly aggressive cancer, HGSC has elevated energy demands to ensure its survival and proliferation in its unique peritoneal environment. Compound C or Dorsomophin is of particular interest as it is the only available cell permeable molecule that works selectively and competitively to inhibit Adenosine Monophosphate Protein-activated protein kinase or AMPK, a sensitive sensor of ATP levels. It has long been established that Compound C has a role as a BMP1 inhibitor during embryogenesis and as an inhibitor of AMPK activity in different contexts. However, the mechanism by which Compound C exerts anti-tumorigenic effects remains unknown. The purpose of this study is to understand how Compound C suppresses growth of HGSC. Our preliminary studies indicate that Compound C inhibits ovarian cancer cell proliferation and survival via a novel mechanism not only through inhibition of AMPK but also through the inhibition of upstream PI3K-Akt as well as TGFβ1/ TGFβ1/2 receptors/Smad 3,4 activation. These findings elucidate a novel mechanism of inhibition of ovarian cancer by Compound C, suggesting its potential use as a novel therapeutic agent inhibiting oncogenic and metabolic pathways.
Citation Format: Alia Ghoneum, Hesham M. Afify, Neveen Said. A novel mechanism of inhibition of ovarian cancer growth by Compound C, dorsomorphin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5445.
Abstract 5448: The role of CLCA2 in cell proliferation and survival of HNSCC—potential biomarker for sensitivity to EGFR inhibitors
Authors: Yin Yufang , Elble Randolph C. 
Published: August 2018

Abstract
Head and neck squamous cell carcinoma (HNSCC) develops in mucous membranes that line the mouth, throat and sinuses. Late stage disease has a poor prognosis, with 5 year survival less than 50%. The epidermal growth factor receptor (EGFR) is overexpressed in more than 90% of HNSCC, and the inhibition of EGFR is an established therapeutic strategy for HNSCC. However, sensitivity to EGFR-targeted therapy cannot be predicted from the expression level of EGFR. Only a subset of HNSCC patients benefit from anti-EGFR targeted therapy, suggesting that additional unknown pathways are involved in EGFR activation. We found that chloride channel accessory 2 (CLCA2) is frequently overexpressed in HNSCC and that its expression level predicts sensitivity to EGFR inhibitors in HNSCC cell lines. Knockdown of CLCA2 in HNSCC cancer cell line Fadu inhibited cell proliferation and sensitized cells to anoikis. Mechanistically, CLCA2 knockdown reduced EGFR signaling, which subsequently attenuated extracellular signal-regulated kinase (ERK). In addition, surface localization of cell-cell adhesion molecule E-cadherin was inhibited, corresponding to reduced cell aggregation. CLCA2 has recently been identified as a positive regulator of store operated calcium influx, and both EGFR activation and E-cadherin surface localization are known to depend on intracellular calcium release. We propose that CLCA2 overexpression in HNSCC allows the cell to better exploit EGFR proliferative signaling and protects from anoikis by promoting cell-cell aggregation. Thus, CLCA2 may serve both as a biomarker for sensitivity to EGFR inhibitors and as a target for inhibition itself.
Citation Format: Yufang Yin, Randolph C. Elble. The role of CLCA2 in cell proliferation and survival of HNSCC—potential biomarker for sensitivity to EGFR inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5448.
Abstract 5455: FDA-approved drug bazedoxifene as a novel inhibitor of IL-6 and IL-11/GP130 signaling for osteosarcoma therapy
Authors: Wu Xiaojuan , Lin Jiayuh 
Published: August 2018

Abstract
Objective: IL-6/IL-11/GP130/STAT3 signaling is crucial for osteosarcoma cells and tumor survival, growth and progression. Here, we show a novel IL-6/GP130 and IL-11/GP130 inhibitor, Bazedoxifene which was reported as a FDA-approved selective estrogen receptor modulator, in osteosarcoma therapy.
Methods: We treated osteosarcoma cells with different concentrations of bazedoxifene and tested expression of GP130/STAT3 signaling and the downstream genes at PCR and protein levels in different cell lines. Furthermore, cell migration and colony formation experiments were done in Bazedoxifene-treated osteosarcoma cells. To determine the in vivo activity of Bazedoxifene, we further tested the efficacy of Bazedoxifene combination treatment with temsirolimus in tumor xenografts generated from the SJSA osteosarcoma cells.
Results: Bazedoxifene appeared specific to IL-6/IL-11 as phosphorylation of STAT1 and STAT3 by IFN-γ and LIF respectively were not affected by the compound. Bazedoxifene inhibited P-STAT3, P-AKT, and induced apoptosis in human osteosarcoma cell lines expressing IL-6 and IL-11. In addition, Bazedoxifene can inhibit colony formation after the drug treatments in cancer cells. This inhibition by Bazedoxifene was partially rescued by IL-6. IFN-γ and IL-4 which do not use GP130 as a receptor and do not induce P-STAT3, did not rescue Bazedoxifene-mediated inhibition. Furthermore, IL-6 but not IFN-γ could rescue the Bazedoxifene-mediated inhibition of cell viability in osteosarcoma cells. Bazedoxifene plus temsirolimus had greater inhibition in growth of SJSA tumor xenografts than single group.
Conclusions: Bazedoxifene is novel and potent IL-6/GP130 and IL-11/GP130 inhibitor and has synergistic effect with temsirolimus treatment in osteosarcoma therapy. Repositioning a drug such as Bazedoxifene already approved for safety by the FDA as a novel inhibitor of IL-6/GP130 and IL-11/GP130 signaling should provide an easier path to clinical trials and have a potential to improve the outcome of osteosarcoma.
Citation Format: Xiaojuan Wu, Jiayuh Lin. FDA-approved drug bazedoxifene as a novel inhibitor of IL-6 and IL-11/GP130 signaling for osteosarcoma therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5455.
Abstract 5465: Resveratrol inhibits cell proliferation via crosstalk between integrin αvβ3 and IGF-1R in primary cell cultures of human uterine fibroids
Authors: Chen Yi-Ru , Shih Ya-Jung , Tang Heng-Yuan Tang , Lin Hung-Yun , Davis Paul J. 
Published: August 2018

Abstract
A uterine fibroid is the most common benign smooth muscle cell tumor of the myometrium. Resveratrol, a stilbene, has been used as an anti-inflammatory and antitumor agent. We aimed to determine the expression of growth factor molecules for growth inhibition after treatment of resveratrol in the primary cell lines from human uterine fibroid. In terms of growth rate, of the 24 uterine fibroid primary cell culture cells, 5 were mildly sensitive, 13 were medium-, and 6 were sensitive to resveratrol treatment. 19 out of the 24 primary cell lines responded to treatment of resveratrol from middle to sensitive ranges. Resveratrol arrested cell proliferation and also induced apoptosis, indicating that an intact apoptotic pathway was present in these cells by resveratrol. Reduction of integrin αvβ3 expression diminished resveratrol-induced antiproliferative effect in uterine fibroid cells. Resveratrol induced the expression of proapoptotic genes such as COX-2 and p21. On the other hand, the expression of proliferative (antiapoptotic) genes was either inhibited in such as BCL2 and CDKN2 or not changed in Cyclin D1 and PCNA. The expression of mRNA and protein of insulin-like growth factor-I (IGF-I) was inhibited by resveratrol in primary uterine fibroid cells. The proapoptotic proteins such as caspase 3 and caspase 9 were activated after resveratrol treatment and demonstrated that resveratrol induced apoptosis in the resveratrol-sensitive primary cell cultures, which was consistent with studies of the flow cytometry. In addition, resveratrol blocked the expression of integrin αvβ3 and protein. Concurrently, constitutive AKT phosphorylation in uterine fibroid cells was inhibited by resveratrol. Therefore, growth modulation of uterine fibroid cells occurs via mechanisms dependent on crosstalk between integrin αvβ3 and IGF-1R. Our findings suggest that resveratrol can be considered as an alternative therapeutic agent for uterine fibroid.
Citation Format: Yi-Ru Chen, Ya-Jung Shih, Heng-Yuan Tang Tang, Hung-Yun Lin, Paul J. Davis. Resveratrol inhibits cell proliferation via crosstalk between integrin αvβ3 and IGF-1R in primary cell cultures of human uterine fibroids [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5465.
Abstract 5474: Activity of the S1P pathway promotes ovarian cancer and serves as a novel metabolic target of metformin
Authors: Hart Peter C. , Chiyoda Tatsuyuki , Curtis Marion , Liu Xiaojing , Chiang Chun-Yi , McGregor Stephanie , Lastra Ricardo , Locasale Jason , Lengyel Ernst , Romero Iris L. 
Published: August 2018

Abstract
Sphingosine-1-phosphate (S1P), a metabolite of the phospholipid sphingosine, is a bioactive lipid that directly interacts with specific G-protein-coupled receptors to transduce signals that regulate growth, proliferation and motility. Sphingosine kinases (SPHK1 and 2) catalyze the formation of S1P from sphingosine, thereby regulating S1P homeostasis and the sphingolipid rheostat. Recently, using TCGA data, we noted SPHK1 amplification in several gynecologic cancers and that high expression of SPHK1 was associated with increased mortality in high-grade serous ovarian cancer (HGSOC). The findings reported here show that exposure of HGSOC tumor cells to exogenous S1P, or overexpression of SPHK1, induced migration, proliferation and clonogenecity in multiple ovarian cancer cell lines in vitro. Likewise, in a xenograft mouse model of ovarian cancer, overexpression of SPHK1 markedly enhanced tumor growth. In prior pre-clinical studies, we have demonstrated a strong protective effect of the diabetes medication metformin in ovarian cancer. Interestingly, we found that patients with HGSOC that use metformin for diabetes have reduced serum S1P levels compared to controls, suggesting that the sphingolipid rheostat may be a novel metabolic target of metformin in ovarian cancer. Supporting this, we identified that SPHK1 expression in ovarian cancer cell lines is reduced by treatment with metformin, and further that the reduction of SPHK1 by metformin was mediated through inhibition of transcriptional activity of hypoxia-inducible factors (HIF1α and HIF2α). Finally, we show that overexpression of SPHK1 in HGSOC cell lines enhanced the cytotoxic effects of metformin. Taken together, our data indicates that hypoxia-induced SPHK1 expression and downstream S1P signaling promote tumor progression in HGSOC, and that tumors utilizing this pathway may be particularly vulnerable to the anti-cancer effects of metformin.
Citation Format: Peter C. Hart, Tatsuyuki Chiyoda, Marion Curtis, Xiaojing Liu, Chun-Yi Chiang, Stephanie McGregor, Ricardo Lastra, Jason Locasale, Ernst Lengyel, Iris L. Romero. Activity of the S1P pathway promotes ovarian cancer and serves as a novel metabolic target of metformin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5474.
Abstract 5479: Targeting fructose-induced metabolic reprogramming in liver metastasis
Authors: Shen Xiling 
Published: August 2018

Abstract
Primary tumors gradually accumulate genetic alterations and are influenced by their microenvironment until they acquire the ability to metastasize to distant organs. Typical of this process, colorectal cancer (CRC) progresses through an adenoma-to-carcinoma sequence that eventually leads to metastasis, preferentially (~70% patients) to the liver. At this phase, the disease becomes challenging to treat and eventually develops resistance to most forms of combination therapy, making CRC metastasis a leading cause of cancer-related deaths. Patients with inoperable liver metastasis respond poorly to chemotherapeutic intervention and have a median survival of 6 to 9 months. Liver lesions have also been shown to seed tertiary tumors in the lungs of patients. Current chemotherapy for advanced CRC does not target liver metastases specifically. This is partly based on observations that CRC metastases are not consistently associated with any specific genetic mutations and they generally resemble cells in the primary tumor. However, emerging evidence suggests that nongenetic alterations, such as epigenetic and metabolic reprogramming, may promote cancer metastasis, including CRC. Targeting such mechanisms may provide a way to enhance therapeutics against metastasis.
In this study, pair-wise analysis of 90 matched samples (normal colon, primary CRC, liver metastasis) from 30 Stage IV CRC patients and an in vivo CRC metastasis model via cecum transplantation suggests that CRC liver metastases alter activity levels of certain metabolic pathways. LC-MS based metabolomics systematically mapped the altered metabolic pathways in CRC liver metastasis. In particular, via hypoxia-responsive GATA6 and fructose-responsive ChREBP, liver metastases upregulate ALDOB, an enzyme involved in fructose metabolism, given that 70% of fructose is metabolized in the liver. Intrahepatic implantation indicates that the liver environment causes CRC cells to upregulate ALDOB. Metabolomics and 13C-labeled fructose tracing studies indicate that ALDOB promotes fructose metabolism to fuel glycolysis, gluconeogenesis and the pentose phosphate pathway. Fructose also triggered downstream signaling to enhance lipid synthesis. ALDOB silencing or dietary fructose restriction suppresses growth of CRC liver metastases, but not primary tumors or lung metastases, highlighting the importance of tumor environment. Our findings suggest that metastatic cells can take advantage of abundant metabolites in their new microenvironment, and manipulation of involved pathways impacts the course of metastatic growth.
Citation Format: Xiling Shen. Targeting fructose-induced metabolic reprogramming in liver metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5479.