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  1. Article ; Online: Induction of endoplasmic reticulum stress as a strategy for melanoma therapy: is there a future?

    Hill, David S / Lovat, Penny E / Haass, Nikolas K

    Melanoma management

    2014  Volume 1, Issue 2, Page(s) 127–137

    Abstract: Melanoma cells employ several survival strategies, including induction of the unfolded protein response, which mediates resistance to endoplasmic reticulum (ER) stress-induced apoptosis. Activation of oncogenes specifically suppresses ER stress-induced ... ...

    Abstract Melanoma cells employ several survival strategies, including induction of the unfolded protein response, which mediates resistance to endoplasmic reticulum (ER) stress-induced apoptosis. Activation of oncogenes specifically suppresses ER stress-induced apoptosis, while upregulation of ER chaperone proteins and antiapoptotic BCL-2 family members increases the protein folding capacity of the cell and the threshold for the induction of ER stress-induced apoptosis, respectively. Modulation of unfolded protein response signaling, inhibition of the protein folding machinery and/or active induction of ER stress may thus represent potential strategies for the therapeutic management of melanoma. To this aim, the present article focuses on the current understanding of how melanoma cells avoid or overcome ER stress-induced apoptosis, as well as therapeutic strategies through which to harness ER stress for therapeutic benefit.
    Language English
    Publishing date 2014-12-04
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 2786852-7
    ISSN 2045-0893 ; 2045-0893
    ISSN (online) 2045-0893
    ISSN 2045-0893
    DOI 10.2217/mmt.14.16
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Targeting the intrinsic apoptosis pathway as a strategy for melanoma therapy.

    Mohana-Kumaran, Nethia / Hill, David S / Allen, John D / Haass, Nikolas K

    Pigment cell & melanoma research

    2014  Volume 27, Issue 4, Page(s) 525–539

    Abstract: Melanoma drug resistance is often attributed to abrogation of the intrinsic apoptosis pathway. Targeting regulators of apoptosis is thus considered a promising approach to sensitizing melanomas to treatment. The development of small-molecule inhibitors ... ...

    Abstract Melanoma drug resistance is often attributed to abrogation of the intrinsic apoptosis pathway. Targeting regulators of apoptosis is thus considered a promising approach to sensitizing melanomas to treatment. The development of small-molecule inhibitors that mimic natural antagonists of either antiapoptotic members of the BCL-2 family or the inhibitor of apoptosis proteins (IAPs), known as BH3- or SMAC-mimetics, respectively, are helping us to understand the mechanisms behind apoptotic resistance. Studies using BH3-mimetics indicate that the antiapoptotic BCL-2 protein MCL-1 and its antagonist NOXA are particularly important regulators of BCL-2 family signaling, while SMAC-mimetic studies show that both XIAP and the cIAPs must be targeted to effectively induce apoptosis of cancer cells. Although most solid tumors, including melanoma, are insensitive to these mimetic drugs as single agents, combinations with other therapeutics have yielded promising results, and tests combining them with BRAF-inhibitors, which have already revolutionized melanoma treatment, are a clear priority.
    MeSH term(s) Animals ; Apoptosis/drug effects ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/therapeutic use ; Humans ; Melanoma/drug therapy ; Melanoma/metabolism ; Melanoma/pathology ; Myeloid Cell Leukemia Sequence 1 Protein/metabolism ; Peptide Fragments/chemistry ; Peptide Fragments/therapeutic use ; Peptidomimetics/chemistry ; Peptidomimetics/therapeutic use ; Proto-Oncogene Proteins/chemistry ; Proto-Oncogene Proteins/therapeutic use ; Proto-Oncogene Proteins B-raf/antagonists & inhibitors ; Proto-Oncogene Proteins B-raf/metabolism ; Proto-Oncogene Proteins c-bcl-2/chemistry ; Proto-Oncogene Proteins c-bcl-2/metabolism ; X-Linked Inhibitor of Apoptosis Protein/metabolism
    Chemical Substances Bax protein (53-86) ; Enzyme Inhibitors ; MCL1 protein, human ; Myeloid Cell Leukemia Sequence 1 Protein ; PMAIP1 protein, human ; Peptide Fragments ; Peptidomimetics ; Proto-Oncogene Proteins ; Proto-Oncogene Proteins c-bcl-2 ; X-Linked Inhibitor of Apoptosis Protein ; XIAP protein, human ; BRAF protein, human (EC 2.7.11.1) ; Proto-Oncogene Proteins B-raf (EC 2.7.11.1)
    Language English
    Publishing date 2014-07
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2409570-9
    ISSN 1755-148X ; 1600-0749 ; 0893-5785 ; 1755-1471
    ISSN (online) 1755-148X ; 1600-0749
    ISSN 0893-5785 ; 1755-1471
    DOI 10.1111/pcmr.12242
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  3. Article ; Online: Cell Cycle Phase-Specific Drug Resistance as an Escape Mechanism of Melanoma Cells.

    Beaumont, Kimberley A / Hill, David S / Daignault, Sheena M / Lui, Goldie Y L / Sharp, Danae M / Gabrielli, Brian / Weninger, Wolfgang / Haass, Nikolas K

    The Journal of investigative dermatology

    2016  Volume 136, Issue 7, Page(s) 1479–1489

    Abstract: The tumor microenvironment is characterized by cancer cell subpopulations with heterogeneous cell cycle profiles. For example, hypoxic tumor zones contain clusters of cancer cells that arrest in G1 phase. It is conceivable that neoplastic cells exhibit ... ...

    Abstract The tumor microenvironment is characterized by cancer cell subpopulations with heterogeneous cell cycle profiles. For example, hypoxic tumor zones contain clusters of cancer cells that arrest in G1 phase. It is conceivable that neoplastic cells exhibit differential drug sensitivity based on their residence in specific cell cycle phases. In this study, we used two-dimensional and organotypic melanoma culture models in combination with fluorescent cell cycle indicators to investigate the effects of cell cycle phases on clinically used drugs. We demonstrate that G1-arrested melanoma cells, irrespective of the underlying cause mediating G1 arrest, are resistant to apoptosis induced by the proteasome inhibitor bortezomib or the alkylating agent temozolomide. In contrast, G1-arrested cells were more sensitive to mitogen-activated protein kinase pathway inhibitor-induced cell death. Of clinical relevance, pretreatment of melanoma cells with a mitogen-activated protein kinase pathway inhibitor, which induced G1 arrest, resulted in resistance to temozolomide or bortezomib. On the other hand, pretreatment with temozolomide, which induced G2 arrest, did not result in resistance to mitogen-activated protein kinase pathway inhibitors. In summary, we established a model to study the effects of the cell cycle on drug sensitivity. Cell cycle phase-specific drug resistance is an escape mechanism of melanoma cells that has implications on the choice and timing of drug combination therapies.
    MeSH term(s) Alkylating Agents/chemistry ; Apoptosis ; Bortezomib/chemistry ; Cell Cycle Checkpoints/drug effects ; Cell Division ; Cyclin-Dependent Kinase Inhibitor p21/metabolism ; Dacarbazine/analogs & derivatives ; Dacarbazine/chemistry ; Drug Resistance, Neoplasm ; G1 Phase ; G2 Phase ; Humans ; MAP Kinase Signaling System ; Melanoma/metabolism ; Mitogen-Activated Protein Kinases/metabolism ; Phosphorylation ; Skin Neoplasms/metabolism ; Temozolomide
    Chemical Substances Alkylating Agents ; Cyclin-Dependent Kinase Inhibitor p21 ; Bortezomib (69G8BD63PP) ; Dacarbazine (7GR28W0FJI) ; Mitogen-Activated Protein Kinases (EC 2.7.11.24) ; Temozolomide (YF1K15M17Y)
    Language English
    Publishing date 2016-03-10
    Publishing country United States
    Document type Journal Article
    ZDB-ID 80136-7
    ISSN 1523-1747 ; 0022-202X
    ISSN (online) 1523-1747
    ISSN 0022-202X
    DOI 10.1016/j.jid.2016.02.805
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Oncogenic BRAF signalling increases Mcl-1 expression in cutaneous metastatic melanoma.

    McKee, Christopher S / Hill, David S / Redfern, Christopher P F / Armstrong, Jane L / Lovat, Penny E

    Experimental dermatology

    2013  Volume 22, Issue 11, Page(s) 767–769

    Abstract: The Bcl-2 family member Mcl-1 is essential for melanoma survival; however, the influence of oncogenic BRAF signalling remains elusive. In this study, Mcl-1 splice variant expression was determined in a panel of melanoma cell lines in relation to BRAF ... ...

    Abstract The Bcl-2 family member Mcl-1 is essential for melanoma survival; however, the influence of oncogenic BRAF signalling remains elusive. In this study, Mcl-1 splice variant expression was determined in a panel of melanoma cell lines in relation to BRAF mutational status. Mcl-1L mRNA expression was increased in melanoma cells compared with primary melanocytes with significantly increased mRNA and protein expression observed in BRAF(V600E) mutant melanoma cells. Although no change in Mcl-1S mRNA was observed, Mcl-1S protein expression also increased in BRAF mutant melanoma cells. Additionally, while over-expression of mutant BRAF(V600E) increased both Mcl-1L and Mcl-1S expression, inhibition of hyperactive BRAF signalling resulted in decreased Mcl-1L expression. These studies suggest that the regulation of Mcl-1 expression by BRAF signalling is increased by oncogenic activation of BRAF, revealing a mechanism of apoptotic resistance which may be overcome by the use of more specifically targeted Mcl-1 inhibitors.
    MeSH term(s) Apoptosis ; Cell Line, Tumor ; Gene Expression Regulation, Neoplastic ; Humans ; Melanocytes/metabolism ; Melanoma/genetics ; Melanoma/metabolism ; Mutation ; Myeloid Cell Leukemia Sequence 1 Protein/metabolism ; Proto-Oncogene Proteins B-raf/metabolism ; Signal Transduction ; Skin Neoplasms/genetics ; Skin Neoplasms/metabolism ; Melanoma, Cutaneous Malignant
    Chemical Substances MCL1 protein, human ; Myeloid Cell Leukemia Sequence 1 Protein ; BRAF protein, human (EC 2.7.11.1) ; Proto-Oncogene Proteins B-raf (EC 2.7.11.1)
    Language English
    Publishing date 2013-10-08
    Publishing country Denmark
    Document type Journal Article
    ZDB-ID 1130936-2
    ISSN 1600-0625 ; 0906-6705
    ISSN (online) 1600-0625
    ISSN 0906-6705
    DOI 10.1111/exd.12254
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    Zs.A 3508: Show issues Location:
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  5. Article ; Online: Real-time cell cycle imaging during melanoma growth, invasion, and drug response.

    Haass, Nikolas K / Beaumont, Kimberley A / Hill, David S / Anfosso, Andrea / Mrass, Paulus / Munoz, Marcia A / Kinjyo, Ichiko / Weninger, Wolfgang

    Pigment cell & melanoma research

    2014  Volume 27, Issue 5, Page(s) 764–776

    Abstract: Solid cancers are composed of heterogeneous zones containing proliferating and quiescent cells. Despite considerable insight into the molecular mechanisms underlying aberrant cell cycle progression, there is limited understanding of the relationship ... ...

    Abstract Solid cancers are composed of heterogeneous zones containing proliferating and quiescent cells. Despite considerable insight into the molecular mechanisms underlying aberrant cell cycle progression, there is limited understanding of the relationship between the cell cycle on the one side, and melanoma cell motility, invasion, and drug sensitivity on the other side. Utilizing the fluorescent ubiquitination-based cell cycle indicator (FUCCI) to longitudinally monitor proliferation and migration of melanoma cells in 3D culture and in vivo, we found that invading melanoma cells cycle actively, while G1-arrested cells showed decreased invasion. Melanoma cells in a hypoxic environment or treated with mitogen-activated protein kinase pathway inhibitors remained G1-arrested for extended periods of time, with proliferation and invasion resuming after re-exposure to a more favorable environment. We challenge the idea that the invasive and proliferative capacity of melanoma cells are mutually exclusive and further demonstrate that a reversibly G1-arrested subpopulation survives in the presence of targeted therapies.
    MeSH term(s) Animals ; Antineoplastic Agents/pharmacology ; Cell Cycle/drug effects ; Cell Hypoxia ; Cell Line, Tumor ; Cell Movement ; Cell Proliferation ; Drug Resistance, Neoplasm ; Female ; Fluorescent Dyes/chemistry ; G1 Phase ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic/drug effects ; HEK293 Cells ; Humans ; MAP Kinase Signaling System ; Melanoma/drug therapy ; Melanoma/metabolism ; Melanoma/pathology ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Neoplasm Invasiveness ; Neoplasm Transplantation ; Ubiquitin/chemistry
    Chemical Substances Antineoplastic Agents ; Fluorescent Dyes ; Ubiquitin
    Language English
    Publishing date 2014-06-27
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2409570-9
    ISSN 1755-148X ; 1600-0749 ; 0893-5785 ; 1755-1471
    ISSN (online) 1755-148X ; 1600-0749
    ISSN 0893-5785 ; 1755-1471
    DOI 10.1111/pcmr.12274
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    Zs.A 2444: Show issues Location:
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  6. Article ; Online: Exploiting cannabinoid-induced cytotoxic autophagy to drive melanoma cell death.

    Armstrong, Jane L / Hill, David S / McKee, Christopher S / Hernandez-Tiedra, Sonia / Lorente, Mar / Lopez-Valero, Israel / Eleni Anagnostou, Maria / Babatunde, Fiyinfoluwa / Corazzari, Marco / Redfern, Christopher P F / Velasco, Guillermo / Lovat, Penny E

    The Journal of investigative dermatology

    2015  Volume 135, Issue 6, Page(s) 1629–1637

    Abstract: Although the global incidence of cutaneous melanoma is increasing, survival rates for patients with metastatic disease remain <10%. Novel treatment strategies are therefore urgently required, particularly for patients bearing BRAF/NRAS wild-type tumors. ... ...

    Abstract Although the global incidence of cutaneous melanoma is increasing, survival rates for patients with metastatic disease remain <10%. Novel treatment strategies are therefore urgently required, particularly for patients bearing BRAF/NRAS wild-type tumors. Targeting autophagy is a means to promote cancer cell death in chemotherapy-resistant tumors, and the aim of this study was to test the hypothesis that cannabinoids promote autophagy-dependent apoptosis in melanoma. Treatment with Δ(9)-Tetrahydrocannabinol (THC) resulted in the activation of autophagy, loss of cell viability, and activation of apoptosis, whereas cotreatment with chloroquine or knockdown of Atg7, but not Beclin-1 or Ambra1, prevented THC-induced autophagy and cell death in vitro. Administration of Sativex-like (a laboratory preparation comprising equal amounts of THC and cannabidiol (CBD)) to mice bearing BRAF wild-type melanoma xenografts substantially inhibited melanoma viability, proliferation, and tumor growth paralleled by an increase in autophagy and apoptosis compared with standard single-agent temozolomide. Collectively, our findings suggest that THC activates noncanonical autophagy-mediated apoptosis of melanoma cells, suggesting that cytotoxic autophagy induction with Sativex warrants clinical evaluation for metastatic disease.
    MeSH term(s) Adaptor Proteins, Signal Transducing/metabolism ; Animals ; Apoptosis ; Apoptosis Regulatory Proteins/metabolism ; Autophagy ; Beclin-1 ; Cannabidiol ; Cannabinoids/chemistry ; Cannabinol/chemistry ; Cell Death ; Cell Line, Tumor ; Cell Proliferation ; Cell Survival ; Dacarbazine/analogs & derivatives ; Dacarbazine/chemistry ; Dronabinol/chemistry ; Drug Combinations ; Humans ; Male ; Melanoma/metabolism ; Melanoma/pathology ; Membrane Proteins/metabolism ; Mice ; Mice, Nude ; Microscopy, Confocal ; Neoplasm Metastasis ; Neoplasm Transplantation ; Neoplasms/metabolism ; Plant Extracts/chemistry ; Proto-Oncogene Proteins B-raf/metabolism ; Skin Neoplasms/metabolism ; Temozolomide ; ras Proteins/metabolism
    Chemical Substances AMBRA1 protein, human ; Adaptor Proteins, Signal Transducing ; Apoptosis Regulatory Proteins ; BECN1 protein, human ; Beclin-1 ; Cannabinoids ; Drug Combinations ; Membrane Proteins ; Plant Extracts ; Cannabidiol (19GBJ60SN5) ; Dacarbazine (7GR28W0FJI) ; Dronabinol (7J8897W37S) ; Cannabinol (7UYP6MC9GH) ; BRAF protein, human (EC 2.7.11.1) ; Proto-Oncogene Proteins B-raf (EC 2.7.11.1) ; ras Proteins (EC 3.6.5.2) ; nabiximols (K4H93P747O) ; Temozolomide (YF1K15M17Y)
    Language English
    Publishing date 2015-02-10
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80136-7
    ISSN 1523-1747 ; 0022-202X
    ISSN (online) 1523-1747
    ISSN 0022-202X
    DOI 10.1038/jid.2015.45
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  7. Article ; Online: A Novel Fully Humanized 3D Skin Equivalent to Model Early Melanoma Invasion.

    Hill, David S / Robinson, Neil D P / Caley, Matthew P / Chen, Mei / O'Toole, Edel A / Armstrong, Jane L / Przyborski, Stefan / Lovat, Penny E

    Molecular cancer therapeutics

    2015  Volume 14, Issue 11, Page(s) 2665–2673

    Abstract: Metastatic melanoma remains incurable, emphasizing the acute need for improved research models to investigate the underlying biologic mechanisms mediating tumor invasion and metastasis, and to develop more effective targeted therapies to improve clinical ...

    Abstract Metastatic melanoma remains incurable, emphasizing the acute need for improved research models to investigate the underlying biologic mechanisms mediating tumor invasion and metastasis, and to develop more effective targeted therapies to improve clinical outcome. Available animal models of melanoma do not accurately reflect human disease and current in vitro human skin equivalent models incorporating melanoma cells are not fully representative of the human skin microenvironment. We have developed a robust and reproducible, fully humanized three-dimensional (3D) skin equivalent comprising a stratified, terminally differentiated epidermis and a dermal compartment consisting of fibroblast-generated extracellular matrix. Melanoma cells incorporated into the epidermis were able to invade through the basement membrane and into the dermis, mirroring early tumor invasion in vivo. Comparison of our novel 3D melanoma skin equivalent with melanoma in situ and metastatic melanoma indicates that this model accurately recreates features of disease pathology, making it a physiologically representative model of early radial and vertical growth-phase melanoma invasion.
    MeSH term(s) 3T3 Cells ; Animals ; Biomarkers, Tumor/metabolism ; Cell Culture Techniques/methods ; Cell Line, Tumor ; Cells, Cultured ; Dermis/metabolism ; Dermis/pathology ; Epidermis/metabolism ; Epidermis/pathology ; Extracellular Matrix/metabolism ; Fibroblasts/metabolism ; Fibroblasts/pathology ; Humans ; MART-1 Antigen/metabolism ; Melanoma/metabolism ; Melanoma/pathology ; Mice ; Microscopy, Electron, Scanning ; Microscopy, Fluorescence ; Models, Biological ; Neoplasm Invasiveness ; Neoplasm Metastasis ; Skin/metabolism ; Skin/pathology ; Skin/ultrastructure ; Skin Neoplasms/metabolism ; Skin Neoplasms/pathology ; Skin, Artificial ; Tumor Microenvironment
    Chemical Substances Biomarkers, Tumor ; MART-1 Antigen
    Language English
    Publishing date 2015-09-01
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2063563-1
    ISSN 1538-8514 ; 1535-7163
    ISSN (online) 1538-8514
    ISSN 1535-7163
    DOI 10.1158/1535-7163.MCT-15-0394
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 5750: Show issues Location:
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  8. Article ; Online: Targeting GRP78 to enhance melanoma cell death.

    Martin, Shaun / Hill, David S / Paton, James C / Paton, Adrienne W / Birch-Machin, Mark A / Lovat, Penny E / Redfern, Chris P F

    Pigment cell & melanoma research

    2010  Volume 23, Issue 5, Page(s) 675–682

    Abstract: Targeting endoplasmic reticulum stress-induced apoptosis may offer an alternative therapeutic strategy for metastatic melanoma. Fenretinide and bortezomib induce apoptosis of melanoma cells but their efficacy may be hindered by the unfolded protein ... ...

    Abstract Targeting endoplasmic reticulum stress-induced apoptosis may offer an alternative therapeutic strategy for metastatic melanoma. Fenretinide and bortezomib induce apoptosis of melanoma cells but their efficacy may be hindered by the unfolded protein response, which promotes survival by ameliorating endoplasmic reticulum stress. The aim of this study was to test the hypothesis that inhibition of GRP78, a vital unfolded protein response mediator, increases cell death in combination with endoplasmic reticulum stress-inducing agents. Down-regulation of GRP78 by small-interfering RNA increased fenretinide- or bortezomib-induced apoptosis. Treatment of cells with a GRP78-specific subtilase toxin produced a synergistic enhancement with fenretinide or bortezomib. These data suggest that combining endoplasmic reticulum stress-inducing agents with strategies to down-regulate GRP78, or other components of the unfolded protein response, may represent a novel therapeutic approach for metastatic melanoma.
    MeSH term(s) Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Boronic Acids/pharmacology ; Boronic Acids/therapeutic use ; Bortezomib ; Cell Death/drug effects ; Cell Line, Tumor ; Endoplasmic Reticulum/metabolism ; Fenretinide/pharmacology ; Fenretinide/therapeutic use ; Heat-Shock Proteins/antagonists & inhibitors ; Heat-Shock Proteins/genetics ; Heat-Shock Proteins/metabolism ; Humans ; Melanoma/drug therapy ; Melanoma/metabolism ; Melanoma/pathology ; Pyrazines/pharmacology ; Pyrazines/therapeutic use ; RNA, Small Interfering/metabolism ; Unfolded Protein Response
    Chemical Substances Antineoplastic Agents ; Boronic Acids ; Heat-Shock Proteins ; Pyrazines ; RNA, Small Interfering ; Fenretinide (187EJ7QEXL) ; Bortezomib (69G8BD63PP) ; molecular chaperone GRP78 (YCYIS6GADR)
    Language English
    Publishing date 2010-07-12
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2409570-9
    ISSN 1755-148X ; 1600-0749 ; 0893-5785 ; 1755-1471
    ISSN (online) 1755-148X ; 1600-0749
    ISSN 0893-5785 ; 1755-1471
    DOI 10.1111/j.1755-148X.2010.00731.x
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  9. Article ; Online: Oncogenic B-RAF signaling in melanoma impairs the therapeutic advantage of autophagy inhibition.

    Armstrong, Jane L / Corazzari, Marco / Martin, Shaun / Pagliarini, Vittoria / Falasca, Laura / Hill, David S / Ellis, Nicola / Al Sabah, Salim / Redfern, Christopher P F / Fimia, Gian Maria / Piacentini, Mauro / Lovat, Penny E

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

    2011  Volume 17, Issue 8, Page(s) 2216–2226

    Abstract: Purpose: Metastatic melanoma is characterized by extremely poor survival rates and hence novel therapies are urgently required. The ability of many anticancer drugs to activate autophagy, a lysosomal-mediated catabolic process which usually promotes ... ...

    Abstract Purpose: Metastatic melanoma is characterized by extremely poor survival rates and hence novel therapies are urgently required. The ability of many anticancer drugs to activate autophagy, a lysosomal-mediated catabolic process which usually promotes cell survival, suggests targeting the autophagy pathway may be a novel means to augment therapy.
    Experimental design: Autophagy and apoptosis were assessed in vitro in human melanoma cell lines in response to clinically achievable concentrations of the endoplasmic reticulum (ER) stress-inducing drugs fenretinide or bortezomib, and in vivo using a s.c. xenograft model.
    Results: Autophagy was activated in response to fenretinide or bortezomib in B-RAF wild-type cells, shown by increased conversion of LC3 to the autophagic vesicle-associated form (LC3-II) and redistribution to autophagosomes and autolysosomes, increased acidic vesicular organelle formation and autophagic vacuolization. In contrast, autophagy was significantly reduced in B-RAF-mutated melanoma cells, an effect attributed partly to oncogenic B-RAF. Rapamycin treatment was unable to stimulate LC3-II accumulation or redistribution in the presence of mutated B-RAF, indicative of de-regulated mTORC1-dependent autophagy. Knockdown of Beclin-1 or ATG7 sensitized B-RAF wild-type cells to fenretinide- or bortezomib-induced cell death, demonstrating a pro-survival function of autophagy. In addition, autophagy was partially reactivated in B-RAF-mutated cells treated with the BH3 mimetic ABT737 in combination with fenretinide or bortezomib, suggesting autophagy resistance is partly mediated by abrogated Beclin-1 function.
    Conclusions: Our findings suggest inhibition of autophagy in combination with ER stress-inducing agents may represent a means by which to harness autophagy for the therapeutic benefit of B-RAF wild-type melanoma.
    MeSH term(s) Animals ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Apoptosis/drug effects ; Autophagy/drug effects ; Biphenyl Compounds/administration & dosage ; Biphenyl Compounds/pharmacology ; Blotting, Western ; Boronic Acids/administration & dosage ; Boronic Acids/pharmacology ; Bortezomib ; Cell Line, Tumor ; Endoplasmic Reticulum/metabolism ; Female ; Fenretinide/administration & dosage ; Fenretinide/pharmacology ; Humans ; Luminescent Proteins/genetics ; Luminescent Proteins/metabolism ; Melanoma/drug therapy ; Melanoma/metabolism ; Melanoma/pathology ; Mice ; Microscopy, Fluorescence ; Microtubule-Associated Proteins/genetics ; Microtubule-Associated Proteins/metabolism ; Nitrophenols/administration & dosage ; Nitrophenols/pharmacology ; Piperazines/administration & dosage ; Piperazines/pharmacology ; Proto-Oncogene Proteins B-raf/genetics ; Proto-Oncogene Proteins B-raf/metabolism ; Pyrazines/administration & dosage ; Pyrazines/pharmacology ; RNA Interference ; Signal Transduction/drug effects ; Sulfonamides/administration & dosage ; Sulfonamides/pharmacology ; Xenograft Model Antitumor Assays
    Chemical Substances ABT-737 ; Biphenyl Compounds ; Boronic Acids ; Luminescent Proteins ; MAP1LC3A protein, human ; Microtubule-Associated Proteins ; Nitrophenols ; Piperazines ; Pyrazines ; Sulfonamides ; Fenretinide (187EJ7QEXL) ; Bortezomib (69G8BD63PP) ; Proto-Oncogene Proteins B-raf (EC 2.7.11.1)
    Language English
    Publishing date 2011-01-26
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1225457-5
    ISSN 1557-3265 ; 1078-0432
    ISSN (online) 1557-3265
    ISSN 1078-0432
    DOI 10.1158/1078-0432.CCR-10-3003
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Targeting X-linked inhibitor of apoptosis protein to increase the efficacy of endoplasmic reticulum stress-induced apoptosis for melanoma therapy.

    Hiscutt, Emma L / Hill, David S / Martin, Shaun / Kerr, Ryan / Harbottle, Andrew / Birch-Machin, Mark / Redfern, Christopher P F / Fulda, Simone / Armstrong, Jane L / Lovat, Penny E

    The Journal of investigative dermatology

    2010  Volume 130, Issue 9, Page(s) 2250–2258

    Abstract: Melanoma remains notoriously resistant to current chemotherapeutics, leaving an acute need for novel therapeutic approaches. The aim of this study was to determine the prognostic and therapeutic significance of X-linked inhibitor of apoptosis protein ( ... ...

    Abstract Melanoma remains notoriously resistant to current chemotherapeutics, leaving an acute need for novel therapeutic approaches. The aim of this study was to determine the prognostic and therapeutic significance of X-linked inhibitor of apoptosis protein (XIAP) in melanoma through correlation of XIAP expression with disease stage, RAS/RAF mutational status, clinical outcome, and susceptibility to endoplasmic reticulum (ER) stress-induced cell death. XIAP expression and N-RAS/B-RAF mutational status were retrospectively determined in a cohort of 55 primary cutaneous melanocytic lesions selected and grouped according to the American Joint Committee on Cancer staging system. Short hairpin RNA interference of XIAP was used to analyze the effect of XIAP expression on ER stress-induced apoptosis in response to fenretinide or bortezomib in vitro. The results showed that XIAP positivity increased with progressive disease stage, although there was no significant correlation between XIAP positivity and combined N-RAS/B-RAF mutational status or clinical outcome. However, XIAP knockdown significantly increased ER stress-induced apoptosis of melanoma cells in a caspase-dependant manner. The correlation of XIAP expression with disease stage, as well as data showing that XIAP knockdown significantly increases fenretinide and bortezomib-induced apoptosis of metastatic melanoma cells, suggests that XIAP may prove to be an effective therapeutic target for melanoma therapy.
    MeSH term(s) Antineoplastic Agents/pharmacology ; Apoptosis/drug effects ; Apoptosis/physiology ; Boronic Acids/pharmacology ; Bortezomib ; Drug Resistance, Neoplasm ; Endoplasmic Reticulum/physiology ; Female ; Fenretinide/pharmacology ; Gene Expression Regulation, Neoplastic ; Genes, ras/physiology ; Humans ; In Vitro Techniques ; Male ; Melanoma/drug therapy ; Melanoma/metabolism ; Melanoma/pathology ; Middle Aged ; Mutation/genetics ; Nevus, Pigmented/drug therapy ; Nevus, Pigmented/metabolism ; Nevus, Pigmented/pathology ; Proto-Oncogene Proteins B-raf/genetics ; Pyrazines/pharmacology ; RNA, Small Interfering ; Skin Neoplasms/drug therapy ; Skin Neoplasms/metabolism ; Skin Neoplasms/pathology ; Stress, Physiological/physiology ; X-Linked Inhibitor of Apoptosis Protein/antagonists & inhibitors ; X-Linked Inhibitor of Apoptosis Protein/genetics ; X-Linked Inhibitor of Apoptosis Protein/metabolism
    Chemical Substances Antineoplastic Agents ; Boronic Acids ; Pyrazines ; RNA, Small Interfering ; X-Linked Inhibitor of Apoptosis Protein ; XIAP protein, human ; Fenretinide (187EJ7QEXL) ; Bortezomib (69G8BD63PP) ; BRAF protein, human (EC 2.7.11.1) ; Proto-Oncogene Proteins B-raf (EC 2.7.11.1)
    Language English
    Publishing date 2010-09
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80136-7
    ISSN 1523-1747 ; 0022-202X
    ISSN (online) 1523-1747
    ISSN 0022-202X
    DOI 10.1038/jid.2010.146
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Ui VI Zs.124: Show issues Location:
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