| Targeting Sphingosine Kinase-1 To Inhibit Melanoma. | |
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MedLine Citation:
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PMID: 22236408 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Resistance to therapies develops rapidly for melanoma leading to more aggressive disease. Therefore, agents are needed that specifically inhibit proteins or pathways controlling the development of this disease, which can be combined, dependent on genes deregulated in a particular patient's tumors. This study shows that elevated sphingosine-1-phosphate (S-1-P) levels resulting from increased activity of sphingosine kinase-1 (SPHK1) occur in advanced melanomas. Targeting SPHK1 using siRNA decreased anchorage dependent and independent growth as well as sensitized melanoma cells to apoptosis inducing agents. Pharmacological SPHK1 inhibitors SKI-I but not SKI-II decreased S-1-P content, elevated ceramide levels, caused a G2-M block and induced apoptotic cell death in melanomas. Targeting SPHK1 using siRNA or the pharmacological agent called SKI-I, decreased the levels of pAKT. Furthermore, SKI-I inhibited the expression of CYCLIN D1 protein and increased the activity of caspase-3/7, which in turn led to the degradation of PARP. In animals, SKI-I but not SKI-II retarded melanoma growth by 25-40%. Thus, targeting SPHK1 using siRNAs or SKI-I has therapeutic potential for melanoma treatment either alone or in combination with other targeted agents. |
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Authors:
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Subbarao V Madhunapantula; Jeremy Hengst; Raghavendra Gowda; Todd E Fox; Jong K Yun; Gavin P Robertson |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-1-11 |
Journal Detail:
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Title: Pigment cell & melanoma research Volume: - ISSN: 1755-148X ISO Abbreviation: - Publication Date: 2012 Jan |
Date Detail:
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Created Date: 2012-1-12 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 101318927 Medline TA: Pigment Cell Melanoma Res Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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Copyright © 2012 John Wiley & Sons A/S. |
Affiliation:
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Departments of Pharmacology Pathology Dermatology Surgery The Foreman Foundation for Melanoma Research Penn State Melanoma Therapeutics Program Penn State Melanoma Center, The Pennsylvania State University College of Medicine, Hershey, PA 17033. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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