bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1699: Suppressor of cytokine signaling 6 (SOCS6) promotes mitochondrial fission through E3 ubiquitin ligase complex activity.
Authors: Lin Huan-Yu , Lin Shiu-Ting , Wang Mei-June , Chen Jeou-Yuan 
Published: August 2014

Abstract
Mitochondria are highly motile organelles that constantly undergo fission and fusion. Impairment of mitochondrial dynamics is associated with mitochondrial dysfunction and is frequently linked to the pathogenesis of neurodegenerative diseases and cancer. We have previously shown that biallelic inactivation of the suppressor of cytokine signaling 6 (SOCS6) is a frequent event in human gastric cancer, and that overexpression of SOCS6 inhibits cell growth as well as colony formation in soft agar, suggesting a potential role of SOCS6 as a tumor suppressor. We also showed that SOCS6 is targeted to mitochondria, and induces mitochondrial fragmentation accompanied with intrinsic apoptosis. SOCS6 induces mitochondrial fragmentation is in part mediated through its interaction with DRP1 and regulation of DRP1 fission activity. In this study, we further showed that SOCS6 interacts with the Elongin B/C and Cullin 5 forming an ECS E3 ubiquitin ligase complex, and that formation of an intact ECS E3 ligase complex is important for SOCS6-mediated mitochondrial fragmentation. First, the interaction of SOCS6 with Elongin B/C and/or Cullin 5 prolonged SOCS6 stability. Second, mutations of the conserved Leu500 and Cys504 residues in SOCS6 BC-box which are critical for Elongin B/C binding yielded a SOCS6 mutant failed to induce mitochondrial fragmentation and apoptosis. Most importantly, ablation of Elongin C activity protected cells from SOCS6-mediated mitochondrial fission. Taken together, our data suggest an important role of SOCS6 in modulating mitochondrial dynamics that is dependent on ECS E3 ubiquitin ligase complex activity.
Citation Format: Huan-Yu Lin, Shiu-Ting Lin, Mei-June Wang, Jeou-Yuan Chen. Suppressor of cytokine signaling 6 (SOCS6) promotes mitochondrial fission through E3 ubiquitin ligase complex activity. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1699. doi:10.1158/1538-7445.AM2013-1699
Abstract 1701: PENAO, a novel mitochondria-targeted agent, has shown potent antitumor effect on glioblastoma in vitro and in vivo.
Authors: Shen Han , Luk Peter P. , Chung Sylvia A. , Decollogne Stephanie , Dilda Pierre J. , Hogg Philip J. , McDonald Kerrie L. 
Published: August 2014

Abstract
Despite advances in multimodal therapy, the prognosis in the great majority of patients with glioblastoma (GBM) is still dismal as almost all tumors relapse and result in disease-related death. New therapeutic strategies are urgently needed. PENAO, (4-(N-(S-penicillaminylacetyl)amino) phenylarsonous acid) is a novel mitochondria-targeted agent that inactivates adenine nucleotide translocase (ANT) located on the inner-membrane of mitochondria. PENAO blocks ANT delivery of ATP to mitochondrial-bound hexokinase II. This blockage inhibits glucose metabolism and triggers the mitochondrial permeability transition pore to leak which results in proliferation arrest and apoptotic cell death.
In vitro, we tested the efficacy of PENAO on a panel of glioblastoma cell lines including immortalized and primary glioblastoma neural stem (GNS) cell lines. PENAO demonstrated potent anti-proliferative activity in all cells. The half-maximal inhibitory concentration (IC50) values for PENAO were in the range of 0.3-6 μM. Blocking ANT with PENAO resulted in inhibition of glioblastoma cell migration at concentration of 1.4 μM. PENAO (0.3-5 μM) increased caspase 3 and 9 activity levels indicative of the intrinsic apoptotic pathway. Proper functioning of ANT is also of importance for maintaining mitochondrial integrity. Low micromolar concentrations of PENAO inhibited oxygen utilization, increased the cytosolic levels of superoxide and depolarized the mitochondrial trans-membrane potential, which are responsible for the activation of mitochondria-mediated apoptosis in glioblastoma cells.
In vivo, PENAO was found to cross the intact blood-brain-barrier in mice and continuous administration of 1 mg/kg/day PENAO to 10 mice bearing subcutaneous glioblastoma tumors for 28 days resulted in 8 partial and 2 complete tumor remissions. No signs or symptoms of treatment toxicity were noticed.
To further inhibit glucose metabolism of glioblastoma, we tested the effectiveness of PENAO in combination with 2-deoxy-D-glucose, a glucose analogue that inhibits glycolysis via competitive inhibition of hexokinase. This dual-targeting of glucose metabolism by inhibiting both mitochondrial respiration and glycolysis led to synergistic effects and improved efficacy when measuring proliferation arrest in vitro. By targeting the glioblastoma aberrant metabolism of glucose better treatments for this cancer may arise.
Citation Format: Han Shen, Peter P. Luk, Sylvia A. Chung, Stephanie Decollogne, Pierre J. Dilda, Philip J. Hogg, Kerrie L. McDonald. PENAO, a novel mitochondria-targeted agent, has shown potent antitumor effect on glioblastoma in vitro and in vivo. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1701. doi:10.1158/1538-7445.AM2013-1701
Abstract 1704: Linking mitochondrial epigenetics to tumorigenesis and the cancer theory of Warburg.
Authors: Seyfried Thomas N. 
Published: August 2014

Abstract
Otto Warburg first proposed that respiratory insufficiency was the common metabolic hallmark of all tumor cells. Respiratory insufficiency is the precursor to aerobic fermentation (Warburg effect), and can also be linked to dysregulated proliferation and to the genomic abnormalities seen in the majority of cancers. It is well documented that tumorigenicity can be suppressed in a broad range of tumor types when cytoplasm from enucleated normal cells, containing normal mitochondria, is fused with nucleated tumor cells to form cybrids. Tumorigenicity is also suppressed in a broad range of tumors following transplantation of the nucleus from tumor cells into enucleated eggs or somatic cells, indicating that tumor nuclei are capable of directing development despite the persistence of tumor-associated mutations. Tumor cell mutations seem to abort development, rather than induce tumorigenesis. In contrast to the tumor suppressive effects of cytoplasm containing normal mitochondria, either cell death or tumor cells arise when nuclei from non-tumorigenic normal cells are fused with cytoplasm from tumor cells. The results from these studies indicate that nuclear genomic defects alone cannot produce tumors, and that normal mitochondria can suppress tumorigenesis. The findings, when viewed collectively, support Warburg's central theory and suggest that mitochondrial epigenetics drives tumorigenesis. Supported in part from the Boston College Res. Expense Fund.
Citation Format: Thomas N. Seyfried. Linking mitochondrial epigenetics to tumorigenesis and the cancer theory of Warburg. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1704. doi:10.1158/1538-7445.AM2013-1704
Abstract 1708: Metabolic regulation of the ubiquitin+proteasome system.
Authors: Driscoll James J. , Jagannathan Sajjeev 
Published: August 2014

Abstract
The ubiquitin+proteasome system (UPS) is a highly complex network that maintains protein homeostasis and cell viability through the highly regulated and selective turnover of targeted proteins. The proteasome is the major intracellular protease in eukaryotes and serves as the catalytic core of the UPS. The cytotoxic effect of proteasome inhibition has been translated therapeutically to dramatically improve the overall survival of patients diagnosed with the plasma cell malignancy multiple myeloma (MM). Bortezomib has emerged as the standard-of-care therapy for MM to catapult the UPS into a position of prominence in cancer biology and drug development but significant obstacles remain since many patients do not respond to bortezomib, clinical responses are not sustained and drug resistance inevitably emerges through unknown mechanisms. Gene profiling was performed as an unbiased approach to address the precise molecular events that promote bortezomib-resistance. Results indicated that effectors of energy metabolism were differentially expressed in cells resistant to bortezomib. Subunits of the cellular energy sensor AMP-activated protein kinase (AMPK) were expressed at lower levels in resistant cells relative to the parental cells. Real-time, cell-based metabolic measurements demonstrated that bortezomib rapidly and dramatically reduced tumor cell oxygen-consumption while bortezomib-resistant cells were less sensitive to metabolic deregulation. Genetic ablation of the AMPKα1/α2 encoding-genes also reduced the effect of bortezomib to promote autophagosome formation as well as bortezomib-induced cytotoxicity. Similarly, knockout of the AMPK-substrate and autophagy-initiating kinase ULK1 also reduced bortezomib-induced autophagosome formation and cell death. Proteasome inhibition promoted ULK-1 association with the autophagosome initiators ATG13, FIP200 and beclin-1. The AMPK activator AICAR further enhanced bortezomib-induced cytotoxicity in myeloma, lymphoma, leukemic and solid tumor cells. Proteasome inhibitors induce AMPK+ULK-mediated autophagosome formation that is coupled to apoptosis and can be exploited as a novel anti-cancer therapeutic strategy.
Citation Format: James J. Driscoll, Sajjeev Jagannathan. Metabolic regulation of the ubiquitin+proteasome system. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1708. doi:10.1158/1538-7445.AM2013-1708
Abstract 1710: An anti-apoptotic Bcl-2 family protein index predicts the response of leukemic cells to the pan-Bcl-2 inhibitor S1.
Authors: Liu Yubo , Zhang Zhichao 
Published: August 2014

Abstract
Bcl-2-like proteins prevent cell death through expression level, post transcriptional modification, and protein-protein-interaction. Recent studies have shown that antiapoptotic Bcl-2-like members are overexpressed in many haematological malignancies. BH3 mimetics are promising anticancer agents by directly target these proteins and their interactions. S1 (8-oxo-3-thiomorpholin-4-yl-8H-acenaphtho[1,2-b]pyrrole-9-carbonitrile) is an authentic BH3 mimetic and a triple inhibitor of Bcl-2, Mcl-1, and Bcl-XL. In the present study, we found S1 exhibited a variant sensitivity with LD50 values ranging &gt;2 logs (0.24-80.4 μM) in five established leukemia cell lines (Jurkat, K562, HL60, U937 and PTA-3920) and forty-one primary leukemic cells (including Acute myeloid leukemia (AML), Acute lymphoblastic leukemia (ALL), Chronic Myeloid Leukemia (CML), and Chronic lymphoblastic leukemia (CLL)). Through a semi-quantitative approach by analyzing western blotting bands via imaging software, it revealed that the index value phosphoralated Bcl-2 (pBcl-2) to Bcl-2 and Mcl-1 provided a highly significant linear correlation with S1 sensitivity (r = 0.69, P &lt; 0.001 in primary cells, and r = 0.76, P = 0.05 in cell lines). In contrast, antiapoptotic Bcl-2-like protein levels, used individually or in combination could not predict S1 sensitivity. Phosphorylated Bcl-2 antagonized S1 by sequestering the Bak and Bim proteins that were released from Mcl-1 in leukemia cell lines. Furthermore, pBcl-2/Bak, pBcl-2/Bax, and pBcl-2/Bim complexes cannot be disrupted by S1. The shift of proapoptotic proteins from being complexed with Mcl-1 to being complexed with pBcl-2 is revealed for the first time, and it could be the mechanism underlying the index value described herein. This study defines the antiapoptotic role of pBcl-2 linked with the protein-protein interaction network within Bcl-2 family.
Citation Format: Yubo Liu, Zhichao Zhang. An anti-apoptotic Bcl-2 family protein index predicts the response of leukemic cells to the pan-Bcl-2 inhibitor S1. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1710. doi:10.1158/1538-7445.AM2013-1710
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 1714: A novel NPM-BAX pathway regulates death evasion and drug sensitivity in human hepatoma cells.
Authors: Hsieh Sen-Yung 
Published: August 2014

Abstract
Death evasion is crucial for both carcinogenesis and resistance to anticancer therapies. Recently we identified nucleophosmin (NPM) as a key factor counteracting death stimuli in human hepatocellular carcinoma (HCC) cells. Here we report the identification of a novel NPM-BCL2-associated X protein (BAX) pathway orchestrating death evasion in human HCC cells. Silencing of NPM expression significantly sensitized HCC cells, particularly those bearing inactivated p53 (Huh7, Hep3B, and Mahlavu), to UV irradiation, mitomycin C, doxorubicin, cisplatin, sorafenib, and lapatinib. This sensitizing effect was not further changed as p53 expression had been simultaneously silenced. Following cell stress, NPM and BAX were induced and exported out of nucleoli and nucleus, respectively. BAX was translocated to cytoplasm in cells with relatively high NPM level, or accumulated in the mitochondria in cells with relatively low NPM level and undergoing apoptosis. Subcellular fractionation revealed that silencing of NPM expression greatly enhanced mitochondrial translocation and oligomerization of BAX in Huh7 and Mahlavu cells. In situ proximity ligation assays and reciprocal co-immunoprecipitation evidenced direct interaction between NPM and BAX in the cytoplasm. Silencing of BAX expression abolished the sensitization effect exerted by silencing of NPM in HCC cells. Clinically, upregulation of NPM was significantly associated with advanced tumor stage and poor prognosis. Conclusion: Via directly blockading BAX mitochondrial translocation and activation, NPM helps human HCC cells evade death induction independently of p53-mediated cell death. Silencing of NPM significantly sensitized HCC cells to anticancer therapies. NPM is a potential co-target in combination with other therapies for HCC particularly harboring inactivated p53. Our findings are of clinical significance, since NPM upregualtion and p53 mutations are usually found in advanced human cancers, including HCC.
Citation Format: Sen-Yung Hsieh. A novel NPM-BAX pathway regulates death evasion and drug sensitivity in human hepatoma cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1714. doi:10.1158/1538-7445.AM2013-1714
Abstract 1720: Maritoclax, a selective Mcl-1 inhibitor, sensitizes melanoma cells to the Bad BH3-mimetic ABT-737.
Authors: Pandey Manoj K. , Gowda Krishne , Doi Kenichiro , Sharma Arun , Wang Hong-Gang , Amin Shantu 
Published: August 2014

Abstract
Melanoma is the most aggressive form of skin cancer. Despite the development of the therapies it remains one of the most invasive and highly drug resistance cancers. The dysregulation of apoptosis are thought to be one barrier to effective systemic treatment of melanoma. The overexpression of anti-apoptotic Bcl-2 family proteins has been associated with inferior survival, poor prognosis and chemoresistance of several cancers including malignant melanoma. ABT-737, a small-molecule inhibitor of Bcl-2, Bcl-xL and Bcl-w, has demonstrated efficacy in several forms of hematological and non-hematological cancers. However, the efficacy of ABT-737 is diminished in cancer cells with high levels of Mcl-1, another anti-apoptotic member of the Bcl-2 family. The overexpression of Mcl-1 is frequently observed in melanoma and therefore, specifically targeting of Mcl-1 may overcome the resistance of ABT-737. In this study, we investigated the effects of Maritoclax, a novel Mcl-1-selective inhibitor, alone and in combination with ABT-737, on the survival of human melanoma cells. The treatments of Maritoclax reduce the cell viabilities of melanoma cells with an IC50 of between 2.2-5.0μM. Further, treatment of melanoma cells with 2.5 μM Maritoclax for 24 h showed significant decrease in Mcl-1 expression. We found that Maritoclax is able to induce apoptosis in melanoma cells in a caspase-dependent manner. Moreover, Maritoclax induces Mcl-1 degradation via the proteasome system, which is associated with its pro-apoptotic activity. Importantly, Maritoclax markedly enhances the efficacy of ABT-737 against melanoma cells. As a single agent, ABT-737 was not efficient in killing UACC 903 cells with IC50 values of &gt;30 μm. However, in combination with a sub-optimal dose of Maritoclax (2.5μM), the efficacy of ABT-737 was enhanced (IC50 1.3 μm). Similarly, Maritoclax potentiated apoptotic effects of ABT-737 from 20%-71% and 18%-62% when measured by Live and Dead and annexin-V assay, respectively. Taken together, these results suggest that targeting of Mcl-1 by Maritoclax may represent a new therapeutic strategy to sensitize melanoma cells to ABT-737-induced apoptosis.
Citation Format: Manoj K. Pandey, Krishne Gowda, Kenichiro Doi, Arun Sharma, Hong-Gang Wang, Shantu Amin. Maritoclax, a selective Mcl-1 inhibitor, sensitizes melanoma cells to the Bad BH3-mimetic ABT-737. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1720. doi:10.1158/1538-7445.AM2013-1720
Abstract 1728: Bcl-XL overexpression prevents B Cell receptor driven autophagy in IgM+ lymphoma.
Authors: Carey Gregory B. , Roy Sanjit K. , Sesay Alphius 
Published: August 2014

Abstract
Our previous studies showed that B cell receptor (BCR) induced apoptosis in lymphoma was preceded by suppression of PI-3K [Carey GB, Scott DW (2001) J. Immunol, 166: 1618-1626]. PI-3K stimulates mTOR, a suppressor of autophagy and mitophagy. In addition, Bcl-XL is known to inhibit BCR-driven apoptosis in lymphoma, although the underlying mechanism is not clear. Therefore the present study examined autophagy in BCR induced apoptosis in lymphoma cells expressing high or low levels of Bcl-XL. WEHI-231 and WEHI-231 cells expressing Bcl-XL (WEHI-231/Bcl-XL) were treated with anti-IgM to cross-link the BCR and to determine the cellular processes leading to apoptosis. The results confirmed dramatic mitochondrial dysfunction followed by apoptosis in parental WEHI-231 compared to WEHI-231/BclXL. BCR-crosslinking resulted in a massive and rapid induction of the autophagic response in parental WEHI-231 compared to those expressing Bcl-XL. Furthermore, treatment with STF-62247, a small molecule inducer of autophagy, resulted in apoptosis in WEHI-231 but not WEHI-231/BclXL cells. These data suggest that BclXL prevents BCR-driven apoptosis in lymphoma via blocking autophagic and mitophagic responses. Hence, combinations of small molecule autophagy inducers and Bcl-XL antagonists may prove to be effective in addressing lymphoma. Supported by NCI Grant UH2CA158689 to G.B.C.
Citation Format: Gregory B. Carey, Sanjit K. Roy, Alphius Sesay. Bcl-XL overexpression prevents B Cell receptor driven autophagy in IgM+ lymphoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1728. doi:10.1158/1538-7445.AM2013-1728
Abstract 1731: Decreased cyclin B1 expression contributes to mitochondrial apoptosis in medulloblastoma.
Authors: Dasari Venkata Ramesh , Asuthkar Swapna , Nalla Arun Kumar , Rao Jasti S. 
Published: August 2014

Abstract
Medulloblastoma, the most common malignant pediatric brain tumor, remains difficult to cure. Previously, we have shown that downregulation of MMP-9 and uPAR induces Chk1-mediated G2/M cell-cycle arrest in medulloblastoma cells. In this study, we observed that downregulation of MMP-9 in nude mice D283 xenografts downregulated the expression of cyclin B1. Increasing evidence indicates that the deregulation of cyclin B1 is involved in neoplastic transformation, suggesting that inhibition of cyclin B1 could be an attractive strategy for anti-tumor therapy. To determine the effect of downregulation of cyclin B1, we treated medulloblastoma cells with nocodazole, which is an anti-neoplastic agent. Nocodazole-treated cells have undergone G2/M cell-cycle arrest because of the mitotic spindle arrest. Prolonged arrest of cells in mitosis due to nocodazole treatment typically results in cell death by apoptosis. Hence, we confirmed the induction of apoptosis in medulloblastoma cells by TUNEL analysis. Immunoblot analysis of cell cycle checkpoint proteins Chk1, Chk2 and cyclin B1 revealed that they were downregulated in combination treatments of shMMP-9 with radiation. Further, apoptotic proteins BAD, BAX and BAK were highly upregulated, which shows the involvement of mitochondria-mediated apoptosis in our treatments. In vivo analysis of BAD molecules in D283 nude mice xenografts confirmed that downregulation of cyclin B1 induces BAD-mediated apoptotic death in medulloblastoma tumors treated with either shMMP-9 alone or in combination with radiation. With this study, we demonstrate that downregulation of cyclin B1 is an effective and specific approach to induce apoptosis for effective anti-tumor therapy against medulloblastoma.
Citation Format: Venkata Ramesh Dasari, Swapna Asuthkar, Arun Kumar Nalla, Jasti S. Rao. Decreased cyclin B1 expression contributes to mitochondrial apoptosis in medulloblastoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1731. doi:10.1158/1538-7445.AM2013-1731