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  1. Article ; Online: Mechanisms regulating glioma invasion.

    Paw, Ivy / Carpenter, Richard C / Watabe, Kounosuke / Debinski, Waldemar / Lo, Hui-Wen

    Cancer letters

    2015  Volume 362, Issue 1, Page(s) 1–7

    Abstract: Glioblastoma (GBM) is the most aggressive, deadliest, and most common brain malignancy in adults. Despite the advances made in surgical techniques, radiotherapy and chemotherapy, the median survival for GBM patients has remained at a mere 14 months. GBM ... ...

    Abstract Glioblastoma (GBM) is the most aggressive, deadliest, and most common brain malignancy in adults. Despite the advances made in surgical techniques, radiotherapy and chemotherapy, the median survival for GBM patients has remained at a mere 14 months. GBM poses several unique challenges to currently available treatments for the disease. For example, GBM cells have the propensity to aggressively infiltrate/invade into the normal brain tissues and along the vascular tracks, which prevents complete resection of all malignant cells and limits the effect of localized radiotherapy while sparing normal tissue. Although anti-angiogenic treatment exerts anti-edematic effect in GBM, unfortunately, tumors progress with acquired increased invasiveness. Therefore, it is an important task to gain a deeper understanding of the intrinsic and post-treatment invasive phenotypes of GBM in hopes that the gained knowledge would lead to novel GBM treatments that are more effective and less toxic. This review will give an overview of some of the signaling pathways that have been shown to positively and negatively regulate GBM invasion, including, the PI3K/Akt, Wnt, sonic hedgehog-GLI1, and microRNAs. The review will also discuss several approaches to cancer therapies potentially altering GBM invasiveness.
    MeSH term(s) Animals ; Brain Neoplasms/metabolism ; Brain Neoplasms/pathology ; Brain Neoplasms/therapy ; Glioblastoma/metabolism ; Glioblastoma/pathology ; Glioblastoma/therapy ; Humans ; Neoplasm Invasiveness
    Language English
    Publishing date 2015-06-28
    Publishing country Ireland
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Review
    ZDB-ID 195674-7
    ISSN 1872-7980 ; 0304-3835
    ISSN (online) 1872-7980
    ISSN 0304-3835
    DOI 10.1016/j.canlet.2015.03.015
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

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  2. Article ; Online: HER2 phosphorylates and destabilizes pro-apoptotic PUMA, leading to antagonized apoptosis in cancer cells.

    Carpenter, Richard L / Han, Woody / Paw, Ivy / Lo, Hui-Wen

    PloS one

    2013  Volume 8, Issue 11, Page(s) e78836

    Abstract: HER2 is overexpressed in 15-20% of breast cancers. HER2 overexpression is known to reduce apoptosis but the underlying mechanisms for this association remain unclear. To elucidate the mechanisms for HER2-mediated survival, we investigated the ... ...

    Abstract HER2 is overexpressed in 15-20% of breast cancers. HER2 overexpression is known to reduce apoptosis but the underlying mechanisms for this association remain unclear. To elucidate the mechanisms for HER2-mediated survival, we investigated the relationship between HER2 and p53 upregulated modulator of apoptosis (PUMA), a potent apoptosis inducer. Our results showed that HER2 interacts with PUMA, which was independent of HER2 activation. In addition, we observed that HER2 interacted with PUMA in both mitochondrial and non-mitochondrial compartments. We next examined whether HER2 phosphorylates PUMA. Notably, PUMA tyrosine phosphorylation has never been reported. Using an intracellular assay, we found PUMA to be phosphorylated in breast cancer cells with activated HER2. Via cell-free HER2 kinase assay, we observed that PUMA was directly phosphorylated by HER2. Activation of HER2 decreased PUMA protein half-life. To identify which of the three tyrosines within PUMA are targeted by HER2, we generated three PUMA non-phosphorylation mutants each with a single Tyr→Phe substitution. Results indicated that each PUMA single mutant had lost some, but not all phosphorylation by HER2 indicating that HER2 targets all three tyrosines. Consequently, we created an additional PUMA mutant with all three tyrosines mutated (TM-PUMA) that could not be phosphorylated by HER2. Importantly, TM-PUMA was found to have a longer half-life than PUMA. An inverse association was observed between HER2 and PUMA in 93 invasive breast carcinoma samples. We further found that TM-PUMA suppressed growth of breast cancer cells to a greater degree than PUMA. Also, TM-PUMA had a stronger propensity to induce apoptosis than PUMA. Together, our results demonstrate, for the first time, that PUMA can be tyrosine phosphorylated and that HER2-mediated phosphorylation destabilizes PUMA protein. The HER2-PUMA interplay represents a novel mechanism by which PUMA is regulated and a new molecular basis for HER2-mediated growth and survival of cancer cells.
    MeSH term(s) Amino Acid Sequence ; Amino Acid Substitution ; Apoptosis ; Apoptosis Regulatory Proteins/genetics ; Apoptosis Regulatory Proteins/metabolism ; Breast Neoplasms ; Cell Proliferation ; Female ; Half-Life ; Humans ; MCF-7 Cells ; Mitochondrial Dynamics ; Molecular Sequence Data ; Phosphorylation ; Protein Binding ; Protein Processing, Post-Translational ; Protein Stability ; Proto-Oncogene Proteins/genetics ; Proto-Oncogene Proteins/metabolism ; Receptor, ErbB-2/physiology
    Chemical Substances Apoptosis Regulatory Proteins ; BBC3 protein, human ; Proto-Oncogene Proteins ; ERBB2 protein, human (EC 2.7.10.1) ; Receptor, ErbB-2 (EC 2.7.10.1)
    Language English
    Publishing date 2013-11-13
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ISSN 1932-6203
    ISSN (online) 1932-6203
    DOI 10.1371/journal.pone.0078836
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: HER2 phosphorylates and destabilizes pro-apoptotic PUMA, leading to antagonized apoptosis in cancer cells.

    Richard L Carpenter / Woody Han / Ivy Paw / Hui-Wen Lo

    PLoS ONE, Vol 8, Iss 11, p e

    2013  Volume 78836

    Abstract: HER2 is overexpressed in 15-20% of breast cancers. HER2 overexpression is known to reduce apoptosis but the underlying mechanisms for this association remain unclear. To elucidate the mechanisms for HER2-mediated survival, we investigated the ... ...

    Abstract HER2 is overexpressed in 15-20% of breast cancers. HER2 overexpression is known to reduce apoptosis but the underlying mechanisms for this association remain unclear. To elucidate the mechanisms for HER2-mediated survival, we investigated the relationship between HER2 and p53 upregulated modulator of apoptosis (PUMA), a potent apoptosis inducer. Our results showed that HER2 interacts with PUMA, which was independent of HER2 activation. In addition, we observed that HER2 interacted with PUMA in both mitochondrial and non-mitochondrial compartments. We next examined whether HER2 phosphorylates PUMA. Notably, PUMA tyrosine phosphorylation has never been reported. Using an intracellular assay, we found PUMA to be phosphorylated in breast cancer cells with activated HER2. Via cell-free HER2 kinase assay, we observed that PUMA was directly phosphorylated by HER2. Activation of HER2 decreased PUMA protein half-life. To identify which of the three tyrosines within PUMA are targeted by HER2, we generated three PUMA non-phosphorylation mutants each with a single Tyr→Phe substitution. Results indicated that each PUMA single mutant had lost some, but not all phosphorylation by HER2 indicating that HER2 targets all three tyrosines. Consequently, we created an additional PUMA mutant with all three tyrosines mutated (TM-PUMA) that could not be phosphorylated by HER2. Importantly, TM-PUMA was found to have a longer half-life than PUMA. An inverse association was observed between HER2 and PUMA in 93 invasive breast carcinoma samples. We further found that TM-PUMA suppressed growth of breast cancer cells to a greater degree than PUMA. Also, TM-PUMA had a stronger propensity to induce apoptosis than PUMA. Together, our results demonstrate, for the first time, that PUMA can be tyrosine phosphorylated and that HER2-mediated phosphorylation destabilizes PUMA protein. The HER2-PUMA interplay represents a novel mechanism by which PUMA is regulated and a new molecular basis for HER2-mediated growth and survival of cancer cells.
    Keywords Medicine ; R ; Science ; Q
    Subject code 610
    Language English
    Publishing date 2013-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: The gain-of-function GLI1 transcription factor TGLI1 enhances expression of VEGF-C and TEM7 to promote glioblastoma angiogenesis.

    Carpenter, Richard L / Paw, Ivy / Zhu, Hu / Sirkisoon, Sherona / Xing, Fei / Watabe, Kounosuke / Debinski, Waldemar / Lo, Hui-Wen

    Oncotarget

    2015  Volume 6, Issue 26, Page(s) 22653–22665

    Abstract: We recently discovered that truncated glioma-associated oncogene homolog 1 (TGLI1) is highly expressed in glioblastoma (GBM) and linked to increased GBM vascularity. The mechanisms underlying TGLI1-mediated angiogenesis are unclear. In this study, we ... ...

    Abstract We recently discovered that truncated glioma-associated oncogene homolog 1 (TGLI1) is highly expressed in glioblastoma (GBM) and linked to increased GBM vascularity. The mechanisms underlying TGLI1-mediated angiogenesis are unclear. In this study, we compared TGLI1- with GLI1-expressing GBM xenografts for the expression profile of 84 angiogenesis-associated genes. The results showed that expression of six genes were upregulated and five were down-regulated in TGLI1-carrying tumors compared to those with GLI1. Vascular endothelial growth factor-C (VEGF-C) and tumor endothelial marker 7 (TEM7) were selected for further investigations because of their significant correlations with high vascularity in 135 patient GBMs. TGLI1 bound to both VEGF-C and TEM7 gene promoters. Conditioned medium from TGLI1-expressing GBM cells strongly induced tubule formation of brain microvascular endothelial cells, and the induction was prevented by VEGF-C/TEM7 knockdown. Immunohistochemical analysis of 122 gliomas showed that TGLI1 expression was positively correlated with VEGF-C, TEM7 and microvessel density. Analysis of NCBI Gene Expression Omnibus datasets with 161 malignant gliomas showed an inverse relationship between tumoral VEGF-C, TEM7 or microvessel density and patient survival. Together, our findings support an important role that TGLI1 plays in GBM angiogenesis and identify VEGF-C and TEM7 as novel TGLI1 target genes of importance to GBM vascularity.
    MeSH term(s) Animals ; Brain Neoplasms/blood supply ; Brain Neoplasms/genetics ; Brain Neoplasms/metabolism ; Cell Line, Tumor ; Glioblastoma/blood supply ; Glioblastoma/genetics ; Glioblastoma/metabolism ; Heterografts ; Humans ; Immunohistochemistry ; Mice ; Mice, Nude ; Neoplasm Proteins/biosynthesis ; Neoplasm Proteins/genetics ; Neovascularization, Pathologic/genetics ; Neovascularization, Pathologic/metabolism ; Neovascularization, Pathologic/pathology ; Receptors, Cell Surface/biosynthesis ; Receptors, Cell Surface/genetics ; Transcription Factors/genetics ; Transcription Factors/metabolism ; Transfection ; Up-Regulation ; Vascular Endothelial Growth Factor C/biosynthesis ; Vascular Endothelial Growth Factor C/genetics ; Zinc Finger Protein GLI1
    Chemical Substances GLI1 protein, human ; Neoplasm Proteins ; PLXDC1 protein, human ; Receptors, Cell Surface ; Transcription Factors ; VEGFC protein, human ; Vascular Endothelial Growth Factor C ; Zinc Finger Protein GLI1
    Language English
    Publishing date 2015-09-08
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2560162-3
    ISSN 1949-2553 ; 1949-2553
    ISSN (online) 1949-2553
    ISSN 1949-2553
    DOI 10.18632/oncotarget.4248
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Combined inhibition of AKT and HSF1 suppresses breast cancer stem cells and tumor growth.

    Carpenter, Richard L / Sirkisoon, Sherona / Zhu, Dongqin / Rimkus, Tadas / Harrison, Alexandria / Anderson, Ashley / Paw, Ivy / Qasem, Shadi / Xing, Fei / Liu, Yin / Chan, Michael / Metheny-Barlow, Linda / Pasche, Boris C / Debinski, Waldemar / Watabe, Kounosuke / Lo, Hui-Wen

    Oncotarget

    2017  Volume 8, Issue 43, Page(s) 73947–73963

    Abstract: Breast cancer is the most common cancer in women and the second leading cause of cancer deaths in women. Over 90% of breast cancer deaths are attributable to metastasis. Our lab has recently reported that AKT activates heat shock factor 1 (HSF1), leading ...

    Abstract Breast cancer is the most common cancer in women and the second leading cause of cancer deaths in women. Over 90% of breast cancer deaths are attributable to metastasis. Our lab has recently reported that AKT activates heat shock factor 1 (HSF1), leading to epithelial-to-mesenchymal transition in HER2-positive breast cancer. However, it is unknown whether the AKT-HSF1 pathway plays an important role in other breast cancer subtypes, breast cancer stem cells, or breast cancer growth and metastasis. Herein, we showed AKT and HSF1 to be frequently co-activated in breast cancer cell lines and specimens across different subtypes. Activated AKT (S473) and HSF1 (S326) are strongly associated with shortened time to metastasis. Inhibition of the AKT-HSF1 signaling axis using small molecule inhibitors, HSF1 knockdown or the dominant-negative HSF1 mutant (S326A) reduced the growth of metastatic breast cancer cells and breast cancer stem cells. The combination of small molecule inhibitors targeting AKT (MK-2206) and HSF1 (KRIBB11) resulted in synergistic killing of breast cancer cells and breast cancer stem cells across different molecular subtypes. Using an orthotopic xenograft mouse model, we found that combined targeting of AKT and HSF1 to significantly reduce tumor growth, induce tumor apoptosis, delay time to metastasis, and prolong host survival. Taken together, our results indicate AKT-HSF1 signaling mediates breast cancer stem cells self-renewal, tumor growth and metastasis, and that dual targeting of AKT and HSF1 resulted in synergistic suppression of breast cancer progression thereby supporting future testing of AKT-HSF1 combination therapy for breast cancer patients.
    Language English
    Publishing date 2017-09-26
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2560162-3
    ISSN 1949-2553 ; 1949-2553
    ISSN (online) 1949-2553
    ISSN 1949-2553
    DOI 10.18632/oncotarget.18166
    Database MEDical Literature Analysis and Retrieval System OnLINE

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