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  1. Article ; Online: Pharmacological and genetic targeting of 5-lipoxygenase interrupts c-Myc oncogenic signaling and kills enzalutamide-resistant prostate cancer cells via apoptosis

    Jitender Monga / Dhatchayini Subramani / Ajay Bharathan / Jagadananda Ghosh

    Scientific Reports, Vol 10, Iss 1, Pp 1-

    2020  Volume 12

    Abstract: Abstract Much of the morbidity and mortality due to prostate cancer happen because of castration-resistant prostate cancer (CRPC) which invariably develops after anti-androgenic therapy. FDA-approved enzalutamide is commonly prescribed for CRPC which ... ...

    Abstract Abstract Much of the morbidity and mortality due to prostate cancer happen because of castration-resistant prostate cancer (CRPC) which invariably develops after anti-androgenic therapy. FDA-approved enzalutamide is commonly prescribed for CRPC which works by blocking androgen receptor function. However, even after initial good response, enzalutamide-resistant prostate cancer (ERPC) develops which eventually leads to widespread metastasis. Management of ERPC is extremely difficult because available therapeutic regimen cannot effectively kill and eliminate ERPC cells. Though the mechanism behind enzalutamide-resistance is not properly understood, over-activation of c-Myc has been found to be a common event which plays an important role in the maintenance and progression of ERPC phenotype. However, direct-targeting of c-Myc poses special problem because of its non-enzymatic nature and certain amount of c-Myc activity is needed by non-cancer cells as well. Thus, c-Myc has emerged as an elusive target which needs to be managed by novel agents and strategies in a cancer-specific way. We investigated the effects of pharmacological and genetic inhibition of 5-lipoxygenase (5-Lox) on cell proliferation, apoptosis and invasive potential of enzalutamide-resistant prostate cancer cells. Transcriptional activity of c-Myc was analyzed by DNA-binding, luciferase-assays, and expression of c-Myc-target genes. We found that 5-Lox regulates c-Myc signaling in enzalutamide-resistant prostate cancer cells and inhibition of 5-Lox by Quiflapon/MK591 or shRNA interrupts oncogenic c-Myc signaling and kills ERPC cells by triggering caspase-mediated apoptosis. Interestingly, MK591 does not affect normal, non-cancer cells in the same experimental conditions. Our findings indicate that inhibition of 5-Lox may emerge as a promising new approach to effectively kill ERPC cells sparing normal cells and suggest that development of a long-term curative therapy of prostate cancer may be possible by killing and eliminating ERPC cells with suitable 5-Lox-inhibitors.
    Keywords Medicine ; R ; Science ; Q
    Subject code 610 ; 500
    Language English
    Publishing date 2020-04-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Pharmacological and genetic targeting of 5-lipoxygenase interrupts c-Myc oncogenic signaling and kills enzalutamide-resistant prostate cancer cells via apoptosis.

    Monga, Jitender / Subramani, Dhatchayini / Bharathan, Ajay / Ghosh, Jagadananda

    Scientific reports

    2020  Volume 10, Issue 1, Page(s) 6649

    Abstract: Much of the morbidity and mortality due to prostate cancer happen because of castration-resistant prostate cancer (CRPC) which invariably develops after anti-androgenic therapy. FDA-approved enzalutamide is commonly prescribed for CRPC which works by ... ...

    Abstract Much of the morbidity and mortality due to prostate cancer happen because of castration-resistant prostate cancer (CRPC) which invariably develops after anti-androgenic therapy. FDA-approved enzalutamide is commonly prescribed for CRPC which works by blocking androgen receptor function. However, even after initial good response, enzalutamide-resistant prostate cancer (ERPC) develops which eventually leads to widespread metastasis. Management of ERPC is extremely difficult because available therapeutic regimen cannot effectively kill and eliminate ERPC cells. Though the mechanism behind enzalutamide-resistance is not properly understood, over-activation of c-Myc has been found to be a common event which plays an important role in the maintenance and progression of ERPC phenotype. However, direct-targeting of c-Myc poses special problem because of its non-enzymatic nature and certain amount of c-Myc activity is needed by non-cancer cells as well. Thus, c-Myc has emerged as an elusive target which needs to be managed by novel agents and strategies in a cancer-specific way. We investigated the effects of pharmacological and genetic inhibition of 5-lipoxygenase (5-Lox) on cell proliferation, apoptosis and invasive potential of enzalutamide-resistant prostate cancer cells. Transcriptional activity of c-Myc was analyzed by DNA-binding, luciferase-assays, and expression of c-Myc-target genes. We found that 5-Lox regulates c-Myc signaling in enzalutamide-resistant prostate cancer cells and inhibition of 5-Lox by Quiflapon/MK591 or shRNA interrupts oncogenic c-Myc signaling and kills ERPC cells by triggering caspase-mediated apoptosis. Interestingly, MK591 does not affect normal, non-cancer cells in the same experimental conditions. Our findings indicate that inhibition of 5-Lox may emerge as a promising new approach to effectively kill ERPC cells sparing normal cells and suggest that development of a long-term curative therapy of prostate cancer may be possible by killing and eliminating ERPC cells with suitable 5-Lox-inhibitors.
    MeSH term(s) 5-Lipoxygenase-Activating Protein Inhibitors/pharmacology ; Antineoplastic Agents/pharmacology ; Apoptosis/drug effects ; Apoptosis/genetics ; Arachidonate 5-Lipoxygenase/genetics ; Arachidonate 5-Lipoxygenase/metabolism ; Benzamides ; Cell Line ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Drug Resistance, Neoplasm/drug effects ; Drug Resistance, Neoplasm/genetics ; Fibroblasts/cytology ; Fibroblasts/drug effects ; Fibroblasts/metabolism ; Gene Expression Regulation, Neoplastic ; Humans ; Indoles/pharmacology ; Male ; Nitriles ; Organ Specificity ; Phenylthiohydantoin/analogs & derivatives ; Phenylthiohydantoin/pharmacology ; Prostate/metabolism ; Prostate/pathology ; Proto-Oncogene Proteins c-myc/genetics ; Proto-Oncogene Proteins c-myc/metabolism ; Quinolines/pharmacology ; RNA, Small Interfering/genetics ; RNA, Small Interfering/metabolism ; Signal Transduction
    Chemical Substances 5-Lipoxygenase-Activating Protein Inhibitors ; Antineoplastic Agents ; Benzamides ; Indoles ; MYC protein, human ; Nitriles ; Proto-Oncogene Proteins c-myc ; Quinolines ; RNA, Small Interfering ; MK 0591 (136668-42-3) ; Phenylthiohydantoin (2010-15-3) ; enzalutamide (93T0T9GKNU) ; Arachidonate 5-Lipoxygenase (EC 1.13.11.34)
    Language English
    Publishing date 2020-04-20
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-020-62845-8
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Integrin-mediated function of Rab GTPases in cancer progression

    Alahari Suresh K / Subramani Dhatchayini

    Molecular Cancer, Vol 9, Iss 1, p

    2010  Volume 312

    Abstract: Abstract The RAS (rat sarcoma) superfamily of small GTPases is broadly subdivided into five groups: Ras, Rho, Rab, Ran, and Arf. Rab family proteins are important in regulating signal transduction and cellular processes such as differentiation, ... ...

    Abstract Abstract The RAS (rat sarcoma) superfamily of small GTPases is broadly subdivided into five groups: Ras, Rho, Rab, Ran, and Arf. Rab family proteins are important in regulating signal transduction and cellular processes such as differentiation, proliferation, vesicle transport, nuclear assembly, and cytoskeleton formation. However, some Rab proteins have been reported to be necessary for the adhesion and migration of cancer cells. Although Ras and Rho family members have been strongly implicated in cancer progression, knowledge of Rabs action in this regard is limited. Some reports have also linked Rab GTPases with cancer cell migration and invasiveness. This review discusses the implications of the involvement of Rabs in malignant transformation and cancer therapy through integrin-mediated signaling events, with particular emphasis on breast cancer.
    Keywords Neoplasms. Tumors. Oncology. Including cancer and carcinogens ; RC254-282 ; Internal medicine ; RC31-1245 ; Medicine ; R ; DOAJ:Oncology ; DOAJ:Medicine (General) ; DOAJ:Health Sciences
    Subject code 610
    Language English
    Publishing date 2010-12-01T00:00:00Z
    Publisher BioMed Central
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Integrin-mediated function of Rab GTPases in cancer progression.

    Subramani, Dhatchayini / Alahari, Suresh K

    Molecular cancer

    2010  Volume 9, Page(s) 312

    Abstract: The RAS (rat sarcoma) superfamily of small GTPases is broadly subdivided into five groups: Ras, Rho, Rab, Ran, and Arf. Rab family proteins are important in regulating signal transduction and cellular processes such as differentiation, proliferation, ... ...

    Abstract The RAS (rat sarcoma) superfamily of small GTPases is broadly subdivided into five groups: Ras, Rho, Rab, Ran, and Arf. Rab family proteins are important in regulating signal transduction and cellular processes such as differentiation, proliferation, vesicle transport, nuclear assembly, and cytoskeleton formation. However, some Rab proteins have been reported to be necessary for the adhesion and migration of cancer cells. Although Ras and Rho family members have been strongly implicated in cancer progression, knowledge of Rabs action in this regard is limited. Some reports have also linked Rab GTPases with cancer cell migration and invasiveness. This review discusses the implications of the involvement of Rabs in malignant transformation and cancer therapy through integrin-mediated signaling events, with particular emphasis on breast cancer.
    MeSH term(s) Animals ; Humans ; Integrins/genetics ; Integrins/metabolism ; Models, Biological ; Neoplasms/enzymology ; Neoplasms/genetics ; Neoplasms/metabolism ; Signal Transduction/genetics ; Signal Transduction/physiology ; rab GTP-Binding Proteins/genetics ; rab GTP-Binding Proteins/metabolism
    Chemical Substances Integrins ; rab GTP-Binding Proteins (EC 3.6.5.2)
    Language English
    Publishing date 2010-12-09
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ISSN 1476-4598
    ISSN (online) 1476-4598
    DOI 10.1186/1476-4598-9-312
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Inter-library loan at ZB MED

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  5. Article ; Online: Serum glutamate levels correlate with Gleason score and glutamate blockade decreases proliferation, migration, and invasion and induces apoptosis in prostate cancer cells.

    Koochekpour, Shahriar / Majumdar, Sunipa / Azabdaftari, Gissou / Attwood, Kristopher / Scioneaux, Ray / Subramani, Dhatchayini / Manhardt, Charles / Lorusso, Giovanni D / Willard, Stacey S / Thompson, Hillary / Shourideh, Mojgan / Rezaei, Katayoon / Sartor, Oliver / Mohler, James L / Vessella, Robert L

    Clinical cancer research : an official journal of the American Association for Cancer Research

    2012  Volume 18, Issue 21, Page(s) 5888–5901

    Abstract: Purpose: During glutaminolysis, glutamine is catabolized to glutamate and incorporated into citric acid cycle and lipogenesis. Serum glutamate levels were measured in patients with primary prostate cancer or metastatic castrate-resistant prostate cancer ...

    Abstract Purpose: During glutaminolysis, glutamine is catabolized to glutamate and incorporated into citric acid cycle and lipogenesis. Serum glutamate levels were measured in patients with primary prostate cancer or metastatic castrate-resistant prostate cancer (mCRPCa) to establish clinical relevance. The effect of glutamate deprivation or blockade by metabotropic glutamate receptor 1 (GRM1) antagonists was investigated on prostate cancer cells' growth, migration, and invasion to establish biologic relevance.
    Experimental design: Serum glutamate levels were measured in normal men (n = 60) and patients with primary prostate cancer (n = 197) or mCRPCa (n = 109). GRM1 expression in prostatic tissues was examined using immunohistochemistry (IHC). Cell growth, migration, and invasion were determined using cell cytotoxicity and modified Boyden chamber assays, respectively. Apoptosis was detected using immunoblotting against cleaved caspases, PARP, and γ-H2AX.
    Results: Univariate and multivariate analyses showed significantly higher serum glutamate levels in Gleason score ≥ 8 than in the Gleason score ≤ 7 and in African Americans than in the Caucasian Americans. African Americans with mCRPCa had significantly higher serum glutamate levels than those with primary prostate cancer or benign prostate. However, in Caucasian Americans, serum glutamate levels were similar in normal research subjects and patients with mCRPC. IHC showed weak or no expression of GRM1 in luminal acinar epithelial cells of normal or hyperplastic glands but high expression in primary or metastatic prostate cancer tissues. Glutamate deprivation or blockade decreased prostate cancer cells' proliferation, migration, and invasion and led to apoptotic cell death.
    Conclusions: Glutamate expression is mechanistically associated with and may provide a biomarker of prostate cancer aggressiveness.
    MeSH term(s) Adult ; African Americans ; Apoptosis/drug effects ; Case-Control Studies ; Cell Line, Tumor ; Cell Movement/drug effects ; Cell Proliferation/drug effects ; European Continental Ancestry Group ; Glutamic Acid/blood ; Humans ; Male ; Middle Aged ; Neoplasm Grading ; Prostate/metabolism ; Prostatic Neoplasms/blood ; Prostatic Neoplasms/metabolism ; Prostatic Neoplasms/pathology ; Receptors, Metabotropic Glutamate/antagonists & inhibitors ; Receptors, Metabotropic Glutamate/metabolism ; Riluzole/pharmacology
    Chemical Substances Receptors, Metabotropic Glutamate ; Glutamic Acid (3KX376GY7L) ; Riluzole (7LJ087RS6F)
    Language English
    Publishing date 2012-10-16
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, P.H.S.
    ZDB-ID 1225457-5
    ISSN 1557-3265 ; 1078-0432
    ISSN (online) 1557-3265
    ISSN 1078-0432
    DOI 10.1158/1078-0432.CCR-12-1308
    Database MEDical Literature Analysis and Retrieval System OnLINE

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