bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4420: Matriptase-mediated proteolytic regulation of biological activity and spatial distribution of PDGF-D
Authors: Huang Wei , Kim Hyeong-Reh C. 
Published: May 2015

Abstract
The oncogenic roles of platelet-derived growth factor D (PDGF-D) and its proteolytic activator, matriptase, have been strongly implicated in human prostate cancer. The latent full-length PDGF-D consists of N-terminal CUB domain, C-terminal growth factor domain, and hinge region in between. Matriptase processes the full-length PDGF-D dimer (FL-D) into PDGF-D growth factor domain dimer (GFD-D) in a step-wise manner, involving generation of hemidimer (HD), which is an intermediate product containing one full-length PDGF-D subunit and one growth factor domain subunit. In this study, we showed that HD acts as a dominant-negative ligand of PDGF/PDGFR signaling in fibroblasts whereas it has its own unique function in pre-osteoclasts. The regulation of PDGF-D's activity by matriptase is biphasic as demonstrated by the event that active PDGF-D GFD-D can be further cleaved into a smaller and yet inactive form if the enzymatic action of matriptase persists. By mutagenesis analyses, we identified amino acid residues R340R341GR343A at the C-terminus of PDGF-D growth factor domain to be the matriptase cleavage site through which PDGF-D is inactivated. Based on the sequence analysis in comparison with the published crystal structure of PDGF-B, we suggest that R340R341GR343A is within the loop III of PDGF-D growth factor domain, a critical domain for its binding to the PDGF receptor. When the positively charged arginine residues of R340R341GR343A were mutated to alanine residues, PDGF-D GFD-D lost its biological activity in activating β-PDGFR. Further, we found that proteolytic processing of latent PDGF-D to remove CUB domain and hinge region is tightly linked with the storage of PDGF-D GFD-D within extracellular matrix (ECM) in vitro. These results indicate the increased affinity to the ECM from FL-D, HD, to GFD-D and also suggest that CUB domain and hinge region of PDGF-D prevent the sequestration of PDGF-D in ECM. Interestingly, the matriptase cleavage site R340R341GR343A within the growth factor domain is also critical for PDGF-D association with ECM. Taken together, the present study reports structural elements crucial to the biologically function of PDGF-D and its association with ECM, suggesting that proteolytic processing is a crucial mechanism for PDGF-D to establish its tissue gradient.
Citation Format: Wei Huang, Hyeong-Reh C. Kim. Matriptase-mediated proteolytic regulation of biological activity and spatial distribution of PDGF-D. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4420. doi:10.1158/1538-7445.AM2014-4420
Abstract 4422: A Hippo-independent pathway modulates YAP-induced resistance of cancer cells to antitubulin drugs
Authors: Zhao Yulei , Khanal Prem , Yang Xiaolong 
Published: May 2015

Abstract
Antitubulin drugs have been widely used for the treatment of various human cancers including breast and lung cancer, etc. Although these drugs are effective as first-line treatment of cancers, many cancer patients are either intrinsically resistant or later develop resistant to drugs, which is one of the major obstacles for successful cancer treatment. Therefore, understanding the molecular mechanism underlying antitubulin drug resistance is critical for future prognosis of cancer treatment and development of novel therapeutic drugs for cancer treatment. The Hippo pathway is an emerging signaling pathway that plays important roles in various biological processes including organ size control, tumorigenesis, stem cell differentiation and renewal, etc. Although tremendous progress has been made toward our understanding of the roles of the Hippo pathway in cancer development, if and how is its role in drug resistance remains largely unknown. Recently, we and others have provided convincing evidence that some core components of the Hippo pathway are involved in the resistance of cancer cells to antitubulin drug Taxol. However, the signaling pathways or genes mediating their effects in chemotherapeutic drug response remain to be identified. In this study, we have discovered that Hippo core component YAP oncoprotein and transcriptional co-activitor is specifically phosphorylated only after treatment of cancer cells with antitubulin drugs. Most significantly, we have identified a Hippo-independent pathway in which activated Cdk1 can directly phosphorylate YAP, which subsequently inactivates YAP function in transactivation and anti-apoptosis during antitubulin drug treatment. These findings have significant implication not only in future use of YAP as a prognostic marker in predicting antitubulin drug response in patients but also provide a novel approach for future targeting and inactivating YAP by activating its phosphorylation for treatment of antitublin drug resistant cancer patients caused by YAP activation.
Citation Format: Yulei Zhao, Prem Khanal, Xiaolong Yang. A Hippo-independent pathway modulates YAP-induced resistance of cancer cells to antitubulin drugs. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4422. doi:10.1158/1538-7445.AM2014-4422
Abstract 4425: Drug resistance via feedback activation of Stat3 in oncogene-addicted cancer cells
Authors: Lee Ho-June , Zhuang Guanglei , Cao Yi , Du Pan , Kim Hyo-Jin , Settleman Jeff 
Published: May 2015

Abstract
Targeted therapy directed against ‘oncogene-addicted’ cancers can produce dramatic responses that are invariably of limited durability due to the emergence of subpopulations of drug-resistant cells. We found that many oncogene-addicted cancer cells treated with pathway-targeted drugs engage a positive feedback loop leading to activation of Stat3, which promotes cell survival, consequently limiting the overall drug response. This was observed in cancer cells driven by diverse mutationally-activated kinases, including EGFR, HER2, ALK, and MET, as well as mutant KRAS. We determined that inhibition of MEK signaling specifically promotes Stat3 engagement. MEK inhibition led to the autocrine-driven activation of Stat3 via the FGF receptor and JAK family kinases, and pharmacological inhibition of MEK together with JAK and FGFR effectively promoted tumor regression in vivo. These findings suggest that inhibition of a Stat3 feedback loop may enhance the response to a broad spectrum of drugs that target pathways of oncogene addiction.
Citation Format: Ho-June Lee, Guanglei Zhuang, Yi Cao, Pan Du, Hyo-Jin Kim, Jeff Settleman. Drug resistance via feedback activation of Stat3 in oncogene-addicted cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4425. doi:10.1158/1538-7445.AM2014-4425
Abstract 4426: Tumor suppressive effects of wild-type Hras on oncogenic Kras-driven pancreatic tumorigenesis
Authors: Weyandt Jamie D. , Counter Christopher M. 
Published: May 2015

Abstract
The RAS proteins are a group of small GTPases that can become constitutively activated by point mutations that are found in a quarter or more of all cancer patients, particularly in pancreatic cancer, in which over 90% of patients have an activating KRAS mutation. There are three well-characterized RAS protein family members: HRAS, NRAS, and KRAS, the latter of which is alternatively spliced at the C-terminus into two proteins, KRAS4A and KRAS4B. The RAS proteins are all nearly identical at their N-termini and core effector binding domains. However, they have divergent C-terminal membrane-binding regions that impart both different subcellular localization and subtle changes in signaling. While oncogenic RAS is well established to promote cancer, recent work has suggested that wild-type RAS proteins also participate in tumorigenesis. In this regard, we previously found that wild-type HRAS is activated downstream of oncogenic KRAS, which promoted tumor growth of human pancreatic cancer cell lines. To examine the role of wild-type Hras during de novo pancreatic tumor development, we tested whether knockout of the wild-type Hras gene altered tumorigenesis in oncogenic Kras-driven mice models of pancreatic cancer. Specifically, Hras homozygous null mice (Hras-/-) were crossed into a Pdx-Cre;LSL-KRasG12D/+ background in the absence or presence of an additional mutant p53 allele (Trp53R172H/+) to induce early and late pancreatic cancer, respectively. Surprisingly, loss of Hras led to an increase in early pancreatic lesions and reduced survival in the model of late disease. Since HRAS is activated downstream of oncogenic KRAS, and high oncogenic signaling can induce a senescent growth arrest, we tested and found that suppressing senescence by mutating both alleles of Trp53 ameliorated the survival difference between wild-type and null Hras mice. We thus hypothesize that wild-type Hras amplifies oncogenic Kras signaling, leading to the growth arrest of senescence and thereby inhibit early tumorigenesis. However, once senescence is suppressed later in tumorigenesis, wild-type RAS proteins instead promote more malignant phenotypes.
Citation Format: Jamie D. Weyandt, Christopher M. Counter. Tumor suppressive effects of wild-type Hras on oncogenic Kras-driven pancreatic tumorigenesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4426. doi:10.1158/1538-7445.AM2014-4426
Abstract 4427: Copper is required for oncogenic BRAF signaling and tumorigenesis
Authors: Brady Donita C. , Crowe Matthew S. , Turski Michelle L. , Hobbs G Aaron , Chaikuad Apirat , Knapp Stefan , Campbell Sharon L. , Thiele Dennis J. , Counter Christopher M. 
Published: May 2015

Abstract
The BRAF serine/threonine kinase is mutated, typically at V600, to induce an active oncogenic state in a large fraction of melanoma, thyroid cancers, hairy cell leukemia, and to a lesser extent, a wide spectrum of other cancers. BRAFV600E in turn activates the kinases MEK1 and MEK2, which stimulates the MAPK pathway to promote cancer. Excitingly, ATP inhibitors of oncogenic BRAF and MEK provide a survival advantage in metastatic melanoma, an effect enhanced by combining the two inhibitors. Thus, combining multiple approaches to inhibit MAPK signaling holds great promise for the treatment of BRAF mutation-positive cancers, especially in terms of overcoming resistance. In this regard, we previously found that copper (Cu) influx enhanced MEK1 phosphorylation of its substrates ERK1/2 through a Cu-MEK1 interaction. We show here that genetic loss of the high affinity Cu transporter Ctr1 or mutations in MEK1 that disrupt Cu binding reduced MAPK signaling and oncogenic BRAFV600E-mediated tumorigenesis, which was rescued by expressing activated MEK5 engineered to phosphorylate ERK1/2 or activated ERK2. Importantly, Cu chelators used in the treatment of Wilson disease reduced tumor growth of not only BRAFV600E-transformed cells but also cells resistant to a BRAF inhibitor. Taken together, these results suggest that Cu-chelation therapy could be repurposed for the treatment of BRAFV600E mutation-positive cancers.
Citation Format: Donita C. Brady, Matthew S. Crowe, Michelle L. Turski, G Aaron Hobbs, Apirat Chaikuad, Stefan Knapp, Sharon L. Campbell, Dennis J. Thiele, Christopher M. Counter. Copper is required for oncogenic BRAF signaling and tumorigenesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4427. doi:10.1158/1538-7445.AM2014-4427
Abstract 4428: Oncogenic ERBB3 mutations in human cancers
Authors: Jaiswal Bijay S. , Kljavin Noelyn M. , Stawiski Eric , Durinck Steffen , Chaudhuri Subhra , Eigenbrot Charles , Schaefer Gabriele , Sauvage Frederic J. de , Seshagiri Somasekar 
Published: May 2015

Abstract
The human epidermal growth factor receptor (HER) family of tyrosine kinases are deregulated in multiple cancers either through amplification, overexpression or mutation. ERBB3/HER3, the only ERBB family member with an impaired kinase domain, upon ligand binding heterodimerizes with ERBB2 to promote signaling. While amplification and overexpression of ERBB3 is observed in some cancers, occurrence and relevance of ERBB3 somatic mutations in oncogenesis is not established. Here we report the identification of ERBB3 somatic mutations in ∼11% of colon and gastric cancers. We found that the ERBB3 mutants together with ERBB2 promote oncogenic signaling and transformed colonic and breast epithelial cells in a ligand independent manner. Further, we found that multiple target therapeutics that acts on ERBB3, ERBB2 or their downstream signaling components are effective in blocking ERBB3-mutant mediated oncogenic signaling and disease progression in vivo. Identification of activating ERBB3 mutations along with the established contribution of ERBB3 to acquired resistance to EGFR/ERBB2-targeted drugs provides a rational to therapeutically target ERBB3.
Citation Format: Bijay S. Jaiswal, Noelyn M. Kljavin, Eric Stawiski, Steffen Durinck, Subhra Chaudhuri, Charles Eigenbrot, Gabriele Schaefer, Frederic J. de Sauvage, Somasekar Seshagiri. Oncogenic ERBB3 mutations in human cancers. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4428. doi:10.1158/1538-7445.AM2014-4428
Abstract 443: Synergistic inhibition of HER2 positive breast cancer by triptolide and lapatinib
Authors: Chalugun Paweena , Shim Joong Sup , Korangath Preethi C. , Sukumar Saraswati , Liu Jun O. 
Published: May 2015

Abstract
HER2-positive breast cancers are poorly differentiated and have a higher potential for metastasis. Although trastuzumab and lapatinib have been used for the treatment of HER2-positive breast cancer, resistance to both drugs has dampened the long-term benefit of those drugs. As cancer has multiple genetic aberrations and can readily develop resistance to individual drugs with specific targets, we employed synergistic drug combination as a strategy to overcome drug resistance and to enhance the efficacy of existing drugs. From a screen of the Johns Hopkins Drug Library, we identified triptolide as a strong synergistic hit with lapatinib in HCC1954, a drug-resistant HER2-positive breast cancer cell line. The combination of lapatinib and nontoxic doses of triptolide synergistically inhibited the HER2 signaling pathway. We found that lapatinib increased both mRNA expression and the half-life of HER2 protein, whereas triptolide countered the effects of lapatinib by downregulating the expression of HER2, leading to synergistic inhibition of the HER2 signaling pathway. The synergy in cell proliferation was observed in all HER2-positive breast cancer cell lines regardless of drug resistance status, but was absent in HER2-negative ones. In mouse xenograft models, the combination of lapatinib and triptolide at their minimum effective doses almost completely inhibited the growth of the drug-resistant HER2-positive breast cancer cells. Together, these findings suggest that the combination of triptolide and lapatinib could be a promising new therapeutic regimen for drug-resistant HER2-positive breast cancer.
Citation Format: Paweena Chalugun, Joong Sup Shim, Preethi C. Korangath, Saraswati Sukumar, Jun O. Liu. Synergistic inhibition of HER2 positive breast cancer by triptolide and lapatinib. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 443. doi:10.1158/1538-7445.AM2014-443
Abstract 4431: N-terminal portion of β-catenin is important in ISGylation of β-catenin by 90K glycoprotein in colorectal cancer cells
Authors: Yoon Somy , Bae Jeong A , Kim Hangun , Moon Kyung-Sub , Kim Kyung Keun 
Published: May 2015

Abstract
β-catenin is a major transducer in Wnt signaling pathway, which is highly expressed in colorectal and other cancers. Previously, we have shown that β-catenin is down-regulated in colorectal cancer cells by glycoprotein, 90K, through ISGylation-dependent ubiquitination. The aim of this study is to further clarify a novel mechanism of β-catenin down-regulation pathway by 90K glycoprotein. To identify ISGylation site of β-catenin, deletion mutants of β-catenin lacking N- or C-terminal domain were employed. As only two lysine residues, K19 and K49, are reside in N-terminus of β-catenin, we sequenced cDNA of β- catenin from paired human colorectal cancer tissues to find the mutation and generated arginine point-mutation. As a result, there is no mutation on K19 and/or K49 in examined specimens and did not affect the 90K-mediated ISGylational degradation. To rule out the possibility of involving non-lysine residue in the ISG15 conjugation, such as serine or threonine, we constructed several deletion mutants and found that none are responsible for the ISG15 conjugation. Now, N-terminal portion of β-catenin is under screening for possible interactions with putative E3 ligases, and further detailed studies delineating the complex formation among ISG15 and β-catenin/E3 ligases are under way.
Citation Format: Somy Yoon, Jeong A Bae, Hangun Kim, Kyung-Sub Moon, Kyung Keun Kim. N-terminal portion of β-catenin is important in ISGylation of β-catenin by 90K glycoprotein in colorectal cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4431. doi:10.1158/1538-7445.AM2014-4431
Abstract 4432: The involvement of suppressor of cytokine signaling 6 (SOCS6) in the ECS E3 ubiquitin ligase complex
Authors: Chen Shu-Chuan , Lin Huan-Yu , Lin Shiu-Ting , Wang Mei-Jung , Chen Jeou-Yuan 
Published: May 2015

Abstract
SOCS proteins were initially identified as the suppressors of cytokine signaling. There are eight members in the SOCS family, each containing a central SH2 domain and a carboxyl-terminal SOCS box motif. Among the SOCS family proteins, CIS and SOCS1-3 have been shown to be expressed at elevated levels upon cytokine treatment, and the up-regulated proteins can then turn around to suppress the cytokine signaling through recruiting the phosphorylated signaling intermediates for ubiquitylation-mediated protein degradation, leading to the blockade of the signaling pathway. However, the involvement of other SOCS family proteins, including SOCS6, in protein ubiquitylation remains to be addressed. We have previously shown that biallelic inactivation of SOCS6 is a frequent event in human gastric cancer, and that overexpression of SOCS6 inhibits cell growth as well as colony formation, suggesting a potential role of SOCS6 as a tumor suppressor. We further demonstrated that SOCS6 is targeted to the mitochondria, and induces mitochondrial fragmentation accompanied with intrinsic apoptosis. In this study, we explored the possible linkage of SOCS6 to the formation of an E3 ubiquitin ligase complex. By GST-pulldown and immunoprecipitation assays, we showed that SOCS6 interacted with Elongin B/C and Cullin 5. At steady state, SOCS6 is expressed at relatively low level, but its level is increased in the presence of proteasome inhibitor MG132. In addition, ectopic expression of Elongin B/C and/or Cullin 5 also led to the stabilization of SOCS6 protein. We also showed that formation of an intact Elongin B/C-Cullin 5-SOCS (ECS) E3 ligase complex is important for SOCS6-mediated mitochondrial fragmentation. Mutations of the conserved Leu500 and Cys504 residues in the BC-box located in SOCS box motif yielded a SOCS6 mutant that not only lost the ability to interact with Elongin B/C but also failed to induce mitochondrial fragmentation and apoptosis. Most importantly, ablation of Elongin C activity protected cells from SOCS6-mediated mitochondrial fission. These data suggest an important role of SOCS6 in modulating mitochondrial dynamics mediated through ECS E3 ubiquitin ligase complex activity. We have also searched for substrates of SOCS6-mediated ECS E3 ubiquitin ligase complex by immunoprecipitation using an anti-K-ϵ-GG antibody followed by proteome study. The characterization of the ubiquitylated candidate proteins will be further discussed.
Note: This abstract was not presented at the meeting.
Citation Format: Shu-Chuan Chen, Huan-Yu Lin, Shiu-Ting Lin, Mei-Jung Wang, Jeou-Yuan Chen. The involvement of suppressor of cytokine signaling 6 (SOCS6) in the ECS E3 ubiquitin ligase complex. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4432. doi:10.1158/1538-7445.AM2014-4432