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  1. Article: Integrated Therapeutic Targeting of the Prostate Tumor Microenvironment.

    Livas, Lydia / Hasani, Sumati / Kyprianou, Natasha

    Advances in experimental medicine and biology

    2021  Volume 1296, Page(s) 183–198

    Abstract: Prostate cancer is a common and deadly cancer among men. The heterogeneity that characterizes prostate tumors contributes to clinical challenges in the diagnosis, prognosis, and treatment of this malignancy. While localized prostate cancer can be treated ...

    Abstract Prostate cancer is a common and deadly cancer among men. The heterogeneity that characterizes prostate tumors contributes to clinical challenges in the diagnosis, prognosis, and treatment of this malignancy. While localized prostate cancer can be treated with surgery or radiotherapy, metastatic disease to the lymph nodes and the bone requires aggressive treatment with androgen deprivation treatment (ADT). Unfortunately, this often eventually progresses to metastatic castration-resistant prostate cancer (mCRPC). Advanced prostate cancer treatment today involves 1st- and 2nd-line taxane chemotherapy and 2nd-generation antiandrogens. The process of epithelial mesenchymal transition (EMT), during which epithelial cells lose their adhesions and their polarity, is a critical contributor to prostate cancer metastasis. In this article, we aim to integrate the current understanding of mechanisms dictating the dynamics of phenotypic EMT, with apoptosis outcomes in prostate tumors in response to antiandrogen and taxane chemotherapy for the treatment of advanced disease. Novel insights into the signaling mechanisms that target the functional interface between apoptosis and EMT will be considered in the context of potential clinical markers of tumor prognosis, as well as for effective therapeutic targeting of α- and β- adrenergic signaling (by novel and existing chemotherapeutic agents and antiandrogens). Interfering with EMT and apoptosis simultaneously toward eradicating the tumor mass is of major significance in combating the lethal disease and increasing patient survival.
    MeSH term(s) Androgen Antagonists/pharmacology ; Androgen Antagonists/therapeutic use ; Drug Resistance, Neoplasm ; Epithelial-Mesenchymal Transition ; Humans ; Male ; Prostatic Neoplasms/drug therapy ; Tumor Microenvironment
    Chemical Substances Androgen Antagonists
    Language English
    Publishing date 2021-06-29
    Publishing country United States
    Document type Journal Article
    ISSN 2214-8019 ; 0065-2598
    ISSN (online) 2214-8019
    ISSN 0065-2598
    DOI 10.1007/978-3-030-59038-3_11
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Inhibition of mitochondrial fission activates glycogen synthesis to support cell survival in colon cancer.

    Hasani, Sumati / Young, Lyndsay E A / Van Nort, Warren / Banerjee, Moumita / Rivas, Dylan R / Kim, Jinhwan / Xiong, Xiaopeng / Sun, Ramon C / Gentry, Matthew S / Sesaki, Hiromi / Gao, Tianyan

    Cell death & disease

    2023  Volume 14, Issue 10, Page(s) 664

    Abstract: Metabolic reprogramming has been recognized as one of the major mechanisms that fuel tumor initiation and progression. Our previous studies demonstrate that activation of Drp1 promotes fatty acid oxidation and downstream Wnt signaling. Here we ... ...

    Abstract Metabolic reprogramming has been recognized as one of the major mechanisms that fuel tumor initiation and progression. Our previous studies demonstrate that activation of Drp1 promotes fatty acid oxidation and downstream Wnt signaling. Here we investigate the role of Drp1 in regulating glycogen metabolism in colon cancer. Knockdown of Drp1 decreases mitochondrial respiration without increasing glycolysis. Analysis of cellular metabolites reveals that the levels of glucose-6-phosphate, a precursor for glycogenesis, are significantly elevated whereas pyruvate and other TCA cycle metabolites remain unchanged in Drp1 knockdown cells. Additionally, silencing Drp1 activates AMPK to stimulate the expression glycogen synthase 1 (GYS1) mRNA and promote glycogen storage. Using 3D organoids from Apc
    MeSH term(s) Humans ; Glycogenolysis ; Cell Survival ; Mitochondrial Dynamics ; Cell Transformation, Neoplastic ; Glycogen/metabolism ; Colonic Neoplasms/genetics ; Dynamins/metabolism
    Chemical Substances Glycogen (9005-79-2) ; Dynamins (EC 3.6.5.5)
    Language English
    Publishing date 2023-10-10
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2541626-1
    ISSN 2041-4889 ; 2041-4889
    ISSN (online) 2041-4889
    ISSN 2041-4889
    DOI 10.1038/s41419-023-06202-3
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Downregulation of PHLPP induced by endoplasmic reticulum stress promotes eIF2α phosphorylation and chemoresistance in colon cancer.

    Guo, Bianqin / Xiong, Xiaopeng / Hasani, Sumati / Wen, Yang-An / Li, Austin T / Martinez, Rebecca / Skaggs, Ashley T / Gao, Tianyan

    Cell death & disease

    2021  Volume 12, Issue 11, Page(s) 960

    Abstract: Aberrant activation of endoplasmic reticulum (ER) stress by extrinsic and intrinsic factors contributes to tumorigenesis and resistance to chemotherapies in various cancer types. Our previous studies have shown that the downregulation of PHLPP, a novel ... ...

    Abstract Aberrant activation of endoplasmic reticulum (ER) stress by extrinsic and intrinsic factors contributes to tumorigenesis and resistance to chemotherapies in various cancer types. Our previous studies have shown that the downregulation of PHLPP, a novel family of Ser/Thr protein phosphatases, promotes tumor initiation, and progression. Here we investigated the functional interaction between the ER stress and PHLPP expression in colon cancer. We found that induction of ER stress significantly decreased the expression of PHLPP proteins through a proteasome-dependent mechanism. Knockdown of PHLPP increased the phosphorylation of eIF2α as well as the expression of autophagy-associated genes downstream of the eIF2α/ATF4 signaling pathway. In addition, results from immunoprecipitation experiments showed that PHLPP interacted with eIF2α and this interaction was enhanced by ER stress. Functionally, knockdown of PHLPP improved cell survival under ER stress conditions, whereas overexpression of a degradation-resistant mutant PHLPP1 had the opposite effect. Taken together, our studies identified ER stress as a novel mechanism that triggers PHLPP downregulation; and PHLPP-loss promotes chemoresistance by upregulating the eIF2α/ATF4 signaling axis in colon cancer cells.
    MeSH term(s) Activating Transcription Factor 4/metabolism ; Autophagy/drug effects ; Cell Line, Tumor ; Cell Survival/drug effects ; Colonic Neoplasms/drug therapy ; Colonic Neoplasms/genetics ; Colonic Neoplasms/pathology ; Down-Regulation/genetics ; Drug Resistance, Neoplasm/genetics ; Endoplasmic Reticulum Stress/drug effects ; Endoplasmic Reticulum Stress/genetics ; Eukaryotic Initiation Factor-2/metabolism ; Gene Expression Regulation, Neoplastic ; Humans ; Irinotecan/pharmacology ; Irinotecan/therapeutic use ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; Phosphoprotein Phosphatases/genetics ; Phosphoprotein Phosphatases/metabolism ; Phosphorylation ; Proteasome Endopeptidase Complex/metabolism ; Proteasome Inhibitors/pharmacology ; Protein Binding/drug effects ; Signal Transduction/drug effects ; Tunicamycin/pharmacology ; Tunicamycin/therapeutic use
    Chemical Substances Eukaryotic Initiation Factor-2 ; Nuclear Proteins ; Proteasome Inhibitors ; Tunicamycin (11089-65-9) ; Activating Transcription Factor 4 (145891-90-3) ; Irinotecan (7673326042) ; PHLPP1 protein, human (EC 3.1.3.16) ; Phosphoprotein Phosphatases (EC 3.1.3.16) ; Proteasome Endopeptidase Complex (EC 3.4.25.1)
    Language English
    Publishing date 2021-10-18
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2541626-1
    ISSN 2041-4889 ; 2041-4889
    ISSN (online) 2041-4889
    ISSN 2041-4889
    DOI 10.1038/s41419-021-04251-0
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Activation of Drp1 promotes fatty acids-induced metabolic reprograming to potentiate Wnt signaling in colon cancer.

    Xiong, Xiaopeng / Hasani, Sumati / Young, Lyndsay E A / Rivas, Dylan R / Skaggs, Ashley T / Martinez, Rebecca / Wang, Chi / Weiss, Heidi L / Gentry, Matthew S / Sun, Ramon C / Gao, Tianyan

    Cell death and differentiation

    2022  Volume 29, Issue 10, Page(s) 1913–1927

    Abstract: Cancer cells are known for their ability to adapt variable metabolic programs depending on the availability of specific nutrients. Our previous studies have shown that uptake of fatty acids alters cellular metabolic pathways in colon cancer cells to ... ...

    Abstract Cancer cells are known for their ability to adapt variable metabolic programs depending on the availability of specific nutrients. Our previous studies have shown that uptake of fatty acids alters cellular metabolic pathways in colon cancer cells to favor fatty acid oxidation. Here, we show that fatty acids activate Drp1 to promote metabolic plasticity in cancer cells. Uptake of fatty acids (FAs) induces mitochondrial fragmentation by promoting ERK-dependent phosphorylation of Drp1 at the S616 site. This increased phosphorylation of Drp1 enhances its dimerization and interaction with Mitochondrial Fission Factor (MFF) at the mitochondria. Consequently, knockdown of Drp1 or MFF attenuates fatty acid-induced mitochondrial fission. In addition, uptake of fatty acids triggers mitophagy via a Drp1- and p62-dependent mechanism to protect mitochondrial integrity. Moreover, results from metabolic profiling analysis reveal that silencing Drp1 disrupts cellular metabolism and blocks fatty acid-induced metabolic reprograming by inhibiting fatty acid utilization. Functionally, knockdown of Drp1 decreases Wnt/β-catenin signaling by preventing fatty acid oxidation-dependent acetylation of β-catenin. As a result, Drp1 depletion inhibits the formation of tumor organoids in vitro and xenograft tumor growth in vivo. Taken together, our study identifies Drp1 as a key mediator that connects mitochondrial dynamics with fatty acid metabolism and cancer cell signaling.
    MeSH term(s) Colonic Neoplasms/genetics ; Dynamins/genetics ; Dynamins/metabolism ; Fatty Acids ; Humans ; Mitochondrial Dynamics/physiology ; Mitochondrial Proteins/genetics ; Mitochondrial Proteins/metabolism ; Phosphorylation ; Wnt Signaling Pathway ; beta Catenin/metabolism
    Chemical Substances Fatty Acids ; Mitochondrial Proteins ; beta Catenin ; Dynamins (EC 3.6.5.5)
    Language English
    Publishing date 2022-03-24
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 1225672-9
    ISSN 1476-5403 ; 1350-9047
    ISSN (online) 1476-5403
    ISSN 1350-9047
    DOI 10.1038/s41418-022-00974-5
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 4230: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)
    Zs.MG 80: Show issues

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  5. Article ; Online: Design and Efficacy of a Monovalent Bispecific PD-1/CTLA4 Antibody That Enhances CTLA4 Blockade on PD-1

    Dovedi, Simon J / Elder, Matthew J / Yang, Chunning / Sitnikova, Suzanne I / Irving, Lorraine / Hansen, Anna / Hair, James / Jones, Des C / Hasani, Sumati / Wang, Bo / Im, Seock-Ah / Tran, Ben / Subramaniam, Deepa S / Gainer, Shelby D / Vashisht, Kapil / Lewis, Arthur / Jin, Xiaofang / Kentner, Stacy / Mulgrew, Kathy /
    Wang, Yaya / Overstreet, Michael G / Dodgson, James / Wu, Yanli / Palazon, Asis / Morrow, Michelle / Rainey, Godfrey J / Browne, Gareth J / Neal, Frances / Murray, Thomas V / Toloczko, Aleksandra D / Dall'Acqua, William / Achour, Ikbel / Freeman, Daniel J / Wilkinson, Robert W / Mazor, Yariv

    Cancer discovery

    2021  Volume 11, Issue 5, Page(s) 1100–1117

    Abstract: The clinical benefit of PD-1 blockade can be improved by combination with CTLA4 inhibition but is commensurate with significant immune-related adverse events suboptimally limiting the doses of anti-CTLA4 mAb that can be used. MEDI5752 is a monovalent ... ...

    Abstract The clinical benefit of PD-1 blockade can be improved by combination with CTLA4 inhibition but is commensurate with significant immune-related adverse events suboptimally limiting the doses of anti-CTLA4 mAb that can be used. MEDI5752 is a monovalent bispecific antibody designed to suppress the PD-1 pathway and provide modulated CTLA4 inhibition favoring enhanced blockade on PD-1
    MeSH term(s) Adenocarcinoma/drug therapy ; Adenocarcinoma, Clear Cell/drug therapy ; Antibodies, Monoclonal, Humanized/therapeutic use ; CTLA-4 Antigen/metabolism ; Humans ; Immunotherapy ; Kidney Neoplasms/drug therapy ; Male ; Middle Aged ; Programmed Cell Death 1 Receptor/metabolism ; Stomach Neoplasms/drug therapy ; T-Lymphocytes/immunology
    Chemical Substances Antibodies, Monoclonal, Humanized ; CTLA-4 Antigen ; CTLA4 protein, human ; Programmed Cell Death 1 Receptor ; Tovetumab (2XY62K75UV)
    Language English
    Publishing date 2021-01-08
    Publishing country United States
    Document type Case Reports ; Journal Article
    ZDB-ID 2625242-9
    ISSN 2159-8290 ; 2159-8274
    ISSN (online) 2159-8290
    ISSN 2159-8274
    DOI 10.1158/2159-8290.CD-20-1445
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 6916: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)

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