Abstract
Rhizochalin is a two-headed sphingolipid-like compound isolated from the sponge Rhizochalina incrustata. It has been reported that rhizocalin and its derivates have a chemopreventive and chemotherapeutic effect. However, the molecular mechanism of these effects is not understood. Here, we demonstrate that aglycon of rhizochalin (AglRhz) from the Rhizochalina incrustata induces AMP-activated protein kinase (AMPK) phosphorylation, and thereby inhibits mammalian target of rapamycin (mTOR)-p70S6 kinase-extracellular signal-regulated kinase (ERK) signaling and activator protein 1 (AP-1) activity via phosphorylation of Raptor in HT-29 cells. In addition, AglRhz induced activation of caspase-3 and poly(ADP-ribose) polymerase (PARP), and DNA fragmentation in HT-29 cells, leads to induction of apoptosis as well as suppression of tumorigenicity of HT-29 cells. Notably, AglRhz inhibits insulin-like growth factor (IGF)-1-induced AP-1 activity and cell transformation in JB6 Cl41 cells. Overall, our findings identify AMPK as an important target protein for mediating the anti-tumor properties of AglRhz in HT-29 colon cancer cells and have important implication for sponges, the most important marine source, in colon cancer.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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AMP-Activated Protein Kinases / genetics
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AMP-Activated Protein Kinases / metabolism*
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Animals
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Antineoplastic Agents / metabolism
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Antineoplastic Agents / pharmacology*
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Antineoplastic Agents / therapeutic use
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Apoptosis / drug effects
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Caspase 3 / metabolism
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Cell Transformation, Neoplastic / drug effects
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Chemoprevention*
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Colonic Neoplasms / drug therapy*
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Colonic Neoplasms / enzymology
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Colonic Neoplasms / genetics
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Colonic Neoplasms / pathology
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DNA Fragmentation / drug effects
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Drug Evaluation, Preclinical
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Fatty Alcohols / metabolism
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Fatty Alcohols / pharmacology*
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Fatty Alcohols / therapeutic use
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Glycosphingolipids / chemistry
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Glycosphingolipids / metabolism
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Glycosphingolipids / pharmacology*
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Glycosphingolipids / therapeutic use
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HT29 Cells
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Humans
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Mice
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Mitogen-Activated Protein Kinases / metabolism
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Molecular Targeted Therapy
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Oceans and Seas
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Phosphorylation
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Phytotherapy
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Plant Preparations / chemistry
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Plant Preparations / isolation & purification
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Plant Preparations / pharmacology
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Poly(ADP-ribose) Polymerases / metabolism
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Porifera
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Protein Serine-Threonine Kinases / metabolism
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TOR Serine-Threonine Kinases / genetics
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TOR Serine-Threonine Kinases / metabolism
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Tetrazolium Salts
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Thiazoles
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Tumor Cells, Cultured
Substances
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Antineoplastic Agents
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Fatty Alcohols
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Glycosphingolipids
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Plant Preparations
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Tetrazolium Salts
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Thiazoles
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rhizochalin A
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rhizochalin aglycon
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Poly(ADP-ribose) Polymerases
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MTOR protein, human
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Protein Serine-Threonine Kinases
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TOR Serine-Threonine Kinases
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Extracellular Signal-Regulated MAP Kinases
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Mitogen-Activated Protein Kinases
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AMP-Activated Protein Kinases
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Caspase 3
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thiazolyl blue