bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3339: The regulatory subunit of PI3K, p85β, induces cellular transformation, enhanced cell proliferation and increased PI3K signaling
Authors: Ito Yoshihiro , Hart Jonathan R. , Ueno Lynn , Vogt Peter K. 
Published: May 2015

Abstract
We have expressed the human p85β in chicken embryo fibroblasts (CEF) using the RCAS retroviral vector. At low concentrations, RCAS-p85β induces the formation of distinct foci of transformed cells. CEF transfected with high concentrations of RCAS-p85β show enhanced cell proliferation and PI3K signaling. RCAS-p85β shares this growth promoting potential with the cancer-derived mutants of p85α, but the wild type p85α protein expressed by the RCAS vector lacks this potential. The transforming and signaling activities of p85β depend on the PI3K catalytic subunit p110. We have used p110 isoform-specific inhibitors to show that the transforming and signaling activities of p85β can be mediated by p110α or p110β or both. This is in contrast to the transforming mutants of p85α which depend almost exclusively on p110α for their growth-promoting effect. p85β can be phosphorylated at Y655. Mutations of the phosphorylation site Y655A or Y655E lose almost all of their transforming and enhanced signaling activity. This result indicates that p85β could be subject to control by tyrosine kinases. Our data document important differences between p85α and p85β and suggest that p85β could carry out special functions in signaling and in cancer.
This work was supported by NIH Grant R01 CA078230. This is abstract 26049 of The Scripps Research Institute.
Citation Format: Yoshihiro Ito, Jonathan R. Hart, Lynn Ueno, Peter K. Vogt. The regulatory subunit of PI3K, p85β, induces cellular transformation, enhanced cell proliferation and increased PI3K signaling. [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 3339. doi:10.1158/1538-7445.AM2014-3339
Abstract 3348: Netrin-4/Integrin beta-4 interaction promotes glioblastoma cell proliferation and protects from temozolomide induced cellular senescence via activating PI3K/AKT pathway
Authors: Hu Yizhou , Ylivinkka Irene , Li Li , Chen Ping , Hautaniemi Sampsa , Nyman Tuula A. , Keski-Oja Jorma Keski-Oja , Hyytiäinen Marko 
Published: May 2015

Abstract
Netrin-4 (NTN4) is a secreted laminin-related protein, which was originally observed to guide neuronal axons during neuronal development. Recently, it has been found to be expressed in many other tissues and tumor types, and to contribute to the regulation of cell adhesion, migration, proliferation, and apoptosis. Glioblastoma multiforme (GBM) is the most common primary tumor of central nervous system (CNS). Although there is no remedy for this fatal disease, the efficacy of temozolomide (TMZ) -an orally taken alkylating agent- has been demonstrated in the treatment of glioblastoma. However, the sensitivity of GBM cells to TMZ is interfered by many factors such as MGMT expression, AKT activation, etc. Here we have explored the functions and molecular mechanisms of NTN4 in GBM.
The suppression of NTN4 expression in GBM cell lines significantly reduced cell proliferation and motility and increased serum deprivation-induced apoptosis. By using tandem affinity purification and mass spectrometric analysis, we identified the physical interaction between integrin beta-4 (ITGB4) and NTN4. This interaction mediates AKT phosphorylation and concomitant mitogenic effects. Furthermore, silencing either NTN4 or ITGB4 in GBM cell induced cellular senescence. Temozolomide induces cellular senescence in MGMT devoid glioma cell lines. Addition of exogenous recombinant NTN4 protein rescued TMZ induced senescence and AKT dephosphorylation in GBM cells in an ITGB4 dependent manner.
Current data suggest that the NTN4-ITGB4 interaction promotes GBM cell proliferation and protects GBM cell from TMZ triggered cellular senescence via activating PI3K/AKT pathway.
Citation Format: Yizhou Hu, Irene Ylivinkka, Li Li, Ping Chen, Sampsa Hautaniemi, Tuula A. Nyman, Jorma Keski-Oja Keski-Oja, Marko Hyytiäinen. Netrin-4/Integrin beta-4 interaction promotes glioblastoma cell proliferation and protects from temozolomide induced cellular senescence via activating PI3K/AKT pathway. [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 3348. doi:10.1158/1538-7445.AM2014-3348
Abstract 3380: Cancer usurps skeletal muscle as an energy repository
Authors: Luo Yi , Yoneda Junya , Ohmori Hitoshi , Sasaki Takamitsu , Kuniyasu Hiroki 
Published: May 2015

Abstract
Cancer cells produce energy through aerobic glycolysis, but contributions of host tissues to cancer energy metabolism is unclear. In this study, we aimed to elucidate the cancer-host energy production relationship, in particular, between cancer energy production and host muscle. During the development and progression of colorectal cancer (CRC), expression of the secreted autophagy-inducing stress protein HMGB1 increased in the muscle of tumor-bearing animals. This effect was associated with decreased expression of pyruvate kinase PKM1 and pyruvate kinase activity in muscle via the HMGB1 receptor RAGE. However, muscle mitochondrial energy production was maintained. In contrast, HMGB1 addition to CRC cells increased lactate fermentation. In the muscle, HMGB1 addition induced autophagy by decreasing levels of active mTOR and increasing autophagy-associated proteins, plasma glutamate and 13C-glutamine incorporation into acetyl-CoA. In a mouse model of colon carcinogenesis, a temporal increase in HMGB1 occurred in serum and colonic mucosa with an increase in autophagy associated with altered plasma free amino acids levels, increased glutamine and decreased PKM1 levels. These differences were abolished by administration of an HMGB1 neutralizing antibody. Similar results were obtained in a mouse xenograft model of human CRC. Taken together, our findings suggest that HMGB1 released during tumorigenesis recruits muscle to supply glutamine to cancer cells as an energy source.
Citation Format: Yi Luo, Junya Yoneda, Hitoshi Ohmori, Takamitsu Sasaki, Hiroki Kuniyasu. Cancer usurps skeletal muscle as an energy repository. [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 3380. doi:10.1158/1538-7445.AM2014-3380
Abstract 4441: Ube2e inhibits the ubiquitination and degradation of EGFR mediated by Cbl and Ube2d
Authors: Ma Ke , Lipkowitz Stanley , Klevit Rachel , Liyasova Mariya Sergeyevna 
Published: May 2015

Abstract
Receptor tyrosine kinases (RTKs) have a demonstrated role as drivers of malignant transformation. Many RTKs (e.g., EGFR, MET, FLT3) are negatively regulated by ubiquitination and degradation mediated by Cbl proteins a family of RING finger (RF) ubiquitin ligases (E3s). There are three mammalian family members Cbl, Cbl-b and Cbl-c. All Cbl proteins have a highly conserved N-terminal tyrosine kinase binding domain and a C3HC4 (RF) domain. Loss of Cbl protein function has be associated with malignant transformation drive by increased RTK activity. E3s such as the Cbl proteins confer specificity to the ubiquitination process and direct the conjugation of ubiquitin to one or more lysines on the specific target proteins in collaboration with ubiquitin-conjugating enzymes (E2s). The E2s bind to the E3 and together they mediate ubiquitination of specific substrates. There are approximately 30 human E2s. All of the E2s have a highly conserved catalytic domain (UBC domain). In this study, we characterized the interaction of Cbl with E2s. Using an in vitro E3 assay, we found that only the Ube2d family (Ube2d1, Ube2d2, and Ube2d3) of E2s mediates autoubiquitination of the three Cbl proteins. Subsequently, using the yeast two-hybrid system, we found that Ube2e1, Ube2e2, Ube2e3, Ube2L3, Ube2u, Ube2w and Ube2z can interact with Cbl even though they do not support autoubiquitination of Cbl in vitro E3 assay. Among these E2s, three Ube2e family members and Ube2w bind to the RF domain of Cbl as demonstrated by the loss of interaction when the RF domain is disrupted. Further, we demonstrated that Ube2e family members are involved in regulation of EGFR activity mediated by Cbl in HeLa cells. Knockdown of Ube2e increases down-regulation and ubiquitination of EGFR in HeLa cells. We further showed that three Ube2e inhibit autoubiquitination of Cbl mediated by Ube2d2 in vitro. Together these data suggest that RTK degradation can be modulated by competition between E2s for the Cbl E3s.
Citation Format: Ke Ma, Stanley Lipkowitz, Rachel Klevit, Mariya Sergeyevna Liyasova. Ube2e inhibits the ubiquitination and degradation of EGFR mediated by Cbl and Ube2d. [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 4441. doi:10.1158/1538-7445.AM2014-4441
Abstract 4463: Targeting SN38 delivery to gastrointestinal cancer cells using a fucose-bound nanoparticle approach
Authors: Kato Junji , Takimoto Rishu , Osuga Takahiro , Ono Michihiro , Hirakawa Masahiro , Yoshida Makoto , Sato Yasushi , Tamura Fumito 
Published: May 2015

Abstract
Background & Aims: Prognosis of patients with metastatic colorectal cancer (CRC) has been improving by introduction of molecular targeting therapy combined with chemotherapeutic agents. However, metastatic CRC still needs new strategies to improve treatment efficacy and survival rate. Increased expression of fucosyltransferases (FUTs) is common in CRC cells. FUTs are key enzymes accelerating malignant transformation through the fucosylation of different sialylated precursors, suggesting a crucial requirement for fucose by metastatic CRC cells. With this in mind, we developed fucose-bound nanoparticles as vehicles for delivery of anticancer drugs specifically to CRC cells. Methods: L-fucose-bound liposomes were produced by the modified cholate dialysis method as vehicles for delivery of Cy5.5, FAM and SN38. The production of CA19-9 was measured by enzyme-linked immunosorbent assay. The CRC cell lines were exposed to SN38 or L-fucose-bound liposomes carrying SN38, and cytotoxicity was monitored with BrdU assay. Introduction of Cy5.5 or FAM by L-fucose-bound liposomes was analyzed by flow cytometry or fluorescence microscopy. The effect of L-fucose-bound liposome carrying SN38 in vivo was analyzed by intravenous injection in mice engrafted with CRC cell lines. All statistical tests were two-sided. Results: L-fucose-bound liposomes containing Cy5.5 or SN38 were effectively delivered into CA19-9 expressing CRC cancer cells. Excess L-fucose decreased the efficiency of Cy5.5 introduction by L-fucose-bound liposomes, suggesting L-fucose-receptor dependency. Intravenously injected L-fucose-bound liposomes carrying SN38 were successfully delivered to CRC cells, mediating efficient tumor growth inhibition as well as prolonging survival in mouse xenograft models. Conclusions: Fucose-bound liposomes carrying anti-cancer drugs should provide a new strategy for patients with colorectal cancer.
Citation Format: Junji Kato, Rishu Takimoto, Takahiro Osuga, Michihiro Ono, Masahiro Hirakawa, Makoto Yoshida, Yasushi Sato, Fumito Tamura. Targeting SN38 delivery to gastrointestinal cancer cells using a fucose-bound nanoparticle approach. [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 4463. doi:10.1158/1538-7445.AM2014-4463
Abstract 4491: FGFR2-ADC potently and selectively inhibits growth of gastric and breast cancer xenograft models
Authors: Sommer Anette , Nising Carl F. , Mahlert Christoph , Kopitz Charlotte C. , Lerchen Hans-Georg , Greven Simone , Stelte-Ludwig Beatrix , Schuhmacher Joachim , Zierz Ruprecht , Wittemer-Rump Sabine , Schatz Christoph , Reetz Frank , Apeler Heiner , Jautelat Rolf , Kreft Bertolt , Ziegelbauer Karl 
Published: May 2015

Abstract
Antibody-drug conjugates (ADCs) represent a promising therapeutic approach for treatment of cancer. We have developed a novel ADC directed against fibroblast growth factor receptor 2 (FGFR2). FGFR2 is overexpressed in several cancer indications, such as gastric cancer and breast cancer, thus representing an interesting therapeutic target for the treatment of FGFR2 positive cancer patients with an ADC-based therapy. The FGFR2-ADC consists of the fully human anti-FGFR2-mAb BAY 1179470 conjugated via a stable linker to a novel auristatin cytotoxic agent (technology licensed from Seattle Genetics). The FGFR2-mAb BAY 1179470, which is cross-reactive with human, mouse, rat and monkey, induces internalization of FGFR2. Quantitative data on FGFR2 antibody bound per cell (ABC) were determined with the QuantiBrite assay using BAY 1179470. FGFR2-ADC has a potency in the single digit nM to sub nM range in a panel of FGFR2-positive cells lines (e.g., SNU-16, KatoIII, SUM52-PE, MFM-223) and shows more than 100-fold selectivity versus FGFR2-negative cell lines. High levels of FGFR2 on cancer cells correlate with internalization efficacy and cytotoxic activity in vitro. FGFR2-ADC is highly efficacious in monotherapy and results in tumor growth inhibition in the gastric cancer xenograft model SNU-16 and tumor regression in the breast cancer xenograft model MFM-223. At doses efficacious in mice, FGFR2-ADC is well tolerated. The pre-clinical efficacy and tolerability data obtained for FGFR2-ADC suggest a therapeutic index and support clinical testing.
Citation Format: Anette Sommer, Carl F. Nising, Christoph Mahlert, Charlotte C. Kopitz, Hans-Georg Lerchen, Simone Greven, Beatrix Stelte-Ludwig, Joachim Schuhmacher, Ruprecht Zierz, Sabine Wittemer-Rump, Christoph Schatz, Frank Reetz, Heiner Apeler, Rolf Jautelat, Bertolt Kreft, Karl Ziegelbauer. FGFR2-ADC potently and selectively inhibits growth of gastric and breast cancer xenograft models. [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 4491. doi:10.1158/1538-7445.AM2014-4491
Abstract 450: Head and neck cancer and HPV infection: A potential role for peritumoral neurogenesis in HPV-associated malignancy
Authors: Graves Christian A. , Tomar Swati , Altomare Diego , Wells James R. , Creek Kim E. , Pirisi Lucia 
Published: May 2015

Abstract
Background: Head and neck cancers account for 5% of all cancer related deaths and present with complex molecular pathology and clinical features owing to their functional anatomical location. The molecular etiology of head and neck squamous cancer (HNSC) has gained extensive attention recently revealing key mutations, viral infection, and an emerging landscape of varying disease sub-types. While perineural invasion has long been associated with poor outcome in HNSC, the association of neurogenesis-related genes with cancer progression has only recently come into focus in HNSC. Using prospectively acquired patient samples and TCGA HNSC mutational analyses we further characterized the sequelae of molecular changes in neurogenesis-related genes and propose that these genes play a significant role in HNSC development.
Methods: All clinical specimens were collected under approval by Institutional Review Board. Prospectively collected samples were analyzed for HPV DNA by linear arrays (InnoLipa) and q-PCR for E7-RNA. Gene expression arrays were conducted to determine differences in HPV activity and neuronal associated gene ontologies (Agilent). Gene expression profiles were compared in oral HPV+ and HPV- cultured oral keratinocytes as well as the TCGA Kandoth & Tang datasets. Gene targets were validated by Immunohistochemistry and qPCR.
Results: Initial unsupervised hierarchical clustering analysis of our HNSC cohort revealed a separation of HPV+ HPV+E7-(HPV-inactive: HPVin), and HPV- tumors with changes in the expression of key neurogenesis-related genes. For example, POU4F1, NGFR, and GRIN2C were significantly up-regulated (P&lt;0.05) in HPV+ vs HPVin cancers. Additional analysis of TCGA data revealed divergence of the mutational spectra in HNSC with and without perineural invasion.
Conclusion: Our preliminary findings indicate the emerging importance of neurogenesis-related genes and perineural involvement in HNSC and support a divergence of HPV+, HPVin, and HPV- HNSC sub-types.
Citation Format: Christian A. Graves, Swati Tomar, Diego Altomare, James R. Wells, Kim E. Creek, Lucia Pirisi. Head and neck cancer and HPV infection: A potential role for peritumoral neurogenesis in HPV-associated malignancy. [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 450. doi:10.1158/1538-7445.AM2014-450
Abstract 4522: Akt2 and acid ceramidase cooperate to induce malignant transformation
Authors: Sebti Said M. , Berndt Norbert , Patel Ronil , Yang Hua , Balasis Maria 
Published: May 2015

Abstract
The ability of Akt 2 and acid ceramidase (ASAH1) to cooperate and induce malignant transformation is not known. Here we show that in immortalized, non-transformed cells, ectopic co-expression of Akt2 and ASAH1 is significantly more effective than expression of each gene alone at inducing cell invasion and at conferring resistance to apoptosis. Consistent with these observations, siRNA-mediated depletion of both Akt2 and ASAH1 is much more potent than depleting each alone at inhibiting cell viability/proliferation and cell invasion. Furthermore, pharmacological inhibitors of Akt (TCN or MK-2206) and ASAH1 (B13) synergize to inhibit cell viability/proliferation, and combinations of these drugs are more effective than single agent treatments at inhibiting cell invasion. Taken together, the results suggest that these two enzymes cooperate to induce malignant transformation and warrant further preclinical studies to evaluate the potential of combining inhibitors of Akt and ASAH1 to treat cancer.
Citation Format: Said M. Sebti, Norbert Berndt, Ronil Patel, Hua Yang, Maria Balasis. Akt2 and acid ceramidase cooperate to induce malignant transformation. [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 4522. doi:10.1158/1538-7445.AM2014-4522
Abstract 4524: Combined inhibition of PIM and PI3 kinases shows an enhanced efficacy in a number of solid tumour cell lines
Authors: O'Neil Michael , Aparicio C. Blanco , Jiang S. , Martinez S. , McKenzie A. , Page Martin , Pastor J. 
Published: May 2015

Abstract
Introduction: PIM kinases play an important role in a number of aspects of the regulation of cell cycle and proliferation. Over expression of PIM kinases is associated with oncogenicity in a number of haematological and solid tumours. Recent evidencesuggests that PIM expression is upregulated by inhibition of signalling on the AKT/PI3K/mTOR pathway. We set out to examine the effects of inhibition of PIM kinases in a number of solid tumor cell lines and to explore the effects of concomitant inhibition of the AKT/PI3K/mTOR pathway with novel agents having dual PIM kinase and PI3k inhibition. Representative cell lines for colorectal, lung, oesophageal and prostate tumors (HCT116, A549 and H460, OE21, PC3 respectively) were chosen for testing in a cytotoxicity assay. Compounds tested were GDC-0941, a prototypical PI3K inhibitor, AZD 1208, a pan-PIM inhibitor (i.e. equi-active on all 3 PIM isoforms), IBL- 201 and IBL-202 (dual-acting PI3K/PIM inhibitors) and IBL-301 and IBL-302 (triple-acting PI3K/PIM/mTOR inhibitors). Rapamycin the prototypical mTOR inhibitor and cisplatin were also tested as reference compounds.
Results: The pan-PIM compound AZD1208 showed efficacy in all cell lines in the micromolar range. Rapamycin was also active across similar concentrations. GDC-0941, the PI3K inhibitor exhibited moderate efficacy across the cell line panel . The dual and triple inhibitors showed cytotoxic effects at sub micromolar concentrations, with the OE21 and PC3 oesophageal and prostate lines respectively showing the most sensitive responses.
Conclusion: These results suggest that in selected solid tumor cell lines combined inhibition of PIM and PI3 kinases can lead to an increased cytotoxic effect. Further studies are under way to determine if this observation is corroborated in vivo. Combined inhibition of PIM and PI3 kinases with a single molecule may offer significant opportunities in the clinic for efficacy in key tumour subsets and to circumvent acquired resistance via feedback mechanisms.
Citation Format: Michael O'Neil, C. Blanco Aparicio, S. Jiang, S. Martinez, A. McKenzie, Martin Page, J. Pastor. Combined inhibition of PIM and PI3 kinases shows an enhanced efficacy in a number of solid tumour cell lines. [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 4524. doi:10.1158/1538-7445.AM2014-4524