Aglycon of rhizochalin from the Rhizochalina incrustata induces apoptosis via activation of AMP-activated protein kinase in HT-29 colon cancer cells

Biol Pharm Bull. 2011;34(10):1553-8. doi: 10.1248/bpb.34.1553.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / genetics
  • AMP-Activated Protein Kinases / metabolism*
  • Animals
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Apoptosis / drug effects
  • Caspase 3 / metabolism
  • Cell Transformation, Neoplastic / drug effects
  • Chemoprevention*
  • Colonic Neoplasms / drug therapy*
  • Colonic Neoplasms / enzymology
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / pathology
  • DNA Fragmentation / drug effects
  • Drug Evaluation, Preclinical
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Fatty Alcohols / metabolism
  • Fatty Alcohols / pharmacology*
  • Fatty Alcohols / therapeutic use
  • Glycosphingolipids / chemistry
  • Glycosphingolipids / metabolism
  • Glycosphingolipids / pharmacology*
  • Glycosphingolipids / therapeutic use
  • HT29 Cells
  • Humans
  • Mice
  • Mitogen-Activated Protein Kinases / metabolism
  • Molecular Targeted Therapy
  • Oceans and Seas
  • Phosphorylation
  • Phytotherapy
  • Plant Preparations / chemistry
  • Plant Preparations / isolation & purification
  • Plant Preparations / pharmacology
  • Poly(ADP-ribose) Polymerases / metabolism
  • Porifera
  • Protein Serine-Threonine Kinases / metabolism
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism
  • Tetrazolium Salts
  • Thiazoles
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents
  • Fatty Alcohols
  • Glycosphingolipids
  • Plant Preparations
  • Tetrazolium Salts
  • Thiazoles
  • rhizochalin A
  • rhizochalin aglycon
  • Poly(ADP-ribose) Polymerases
  • MTOR protein, human
  • Protein Serine-Threonine Kinases
  • TOR Serine-Threonine Kinases
  • Extracellular Signal-Regulated MAP Kinases
  • Mitogen-Activated Protein Kinases
  • AMP-Activated Protein Kinases
  • Caspase 3
  • thiazolyl blue