Abstract
Prostate cancer is one of the most frequently diagnosed cancers in human males. Progression of these tumors is facilitated by autocrine/paracrine growth factors which activate critical signaling cascades that promote prostate cancer cell growth, survival and migration. Among these, Ras pathways have a major role. Here we examined the effect of the Ras inhibitor S-trans, trans-farnesylthiosalicylic acid (FTS), on growth and viability of androgen-dependent and androgen-independent prostate cancer cells. FTS downregulated Ras, inhibited signaling to Akt and reduced the levels of cell-cycle regulatory proteins including cyclin D1, p-RB, E2F-1 and cdc42 in LNCaP and PC3 cells. Consequently the anchorage-dependent and anchorage-independent growth of LNCaP and PC3 cells were inhibited. FTS also induced apoptotic cell death which was inhibited by the broad-spectrum caspases inhibitor, Boc-asp-FMK. Our study demonstrated that androgen-dependent and androgen-independent prostate cancer cells require active Ras for growth and survival. Ras inhibition by FTS results in growth arrest and cell death. FTS may be qualified as a potential agent for the treatment of prostate cancer.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Chloromethyl Ketones / pharmacology
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Androgens / physiology*
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Antineoplastic Agents / pharmacology
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Apoptosis / drug effects*
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Cell Cycle / drug effects
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Cell Cycle Proteins / metabolism
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Cell Line, Tumor
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Cell Proliferation / drug effects*
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Cell Survival / drug effects
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Cyclin D1 / metabolism
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Dose-Response Relationship, Drug
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Down-Regulation / drug effects
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E2F1 Transcription Factor / metabolism
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Farnesol / analogs & derivatives*
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Farnesol / pharmacology
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Humans
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Male
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Myotonin-Protein Kinase
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Prostatic Neoplasms / metabolism
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Prostatic Neoplasms / pathology
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Protein-Tyrosine Kinases / metabolism
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Proto-Oncogene Proteins c-akt / metabolism
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Salicylates / pharmacology*
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Serine Proteinase Inhibitors / pharmacology
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Signal Transduction / drug effects
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ras Proteins / antagonists & inhibitors*
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ras Proteins / metabolism
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ras Proteins / physiology
Substances
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Amino Acid Chloromethyl Ketones
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Androgens
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Antineoplastic Agents
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Cell Cycle Proteins
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E2F1 Transcription Factor
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Salicylates
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Serine Proteinase Inhibitors
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butyloxycarbonyl-aspartyl-fluoromethyl ketone
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farnesylthiosalicylic acid
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Cyclin D1
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Farnesol
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CDC42BPB protein, human
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Protein-Tyrosine Kinases
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Myotonin-Protein Kinase
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Proto-Oncogene Proteins c-akt
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ras Proteins