Lunasin potentiates the effect of oxaliplatin preventing outgrowth of colon cancer metastasis, binds to α5β1 integrin and suppresses FAK/ERK/NF-κB signaling

Cancer Lett. 2011 Dec 27;313(2):167-80. doi: 10.1016/j.canlet.2011.09.002. Epub 2011 Sep 10.

Abstract

The effect of lunasin on colon cancer metastasis was studied using three human colon cancer cell lines in vitro and a liver metastasis model of colon cancer in vivo. Lunasin bound with α5β1 integrin and internalized into the nucleus of KM12L4 human colon cancer cells. Lunasin (10 μM) inhibited the activation of focal adhesion kinase (FAK) by 28%, 39% and 60% in RKO, HCT-116 and KM12L4 human colon cancer cells, respectively. Lunasin caused an increase in the expression of the inhibitor of kappa B alpha (IκB-α), a decrease in nuclear p50 NF-κB and a reduction in the migration of cancer cells. Lunasin (4 mg/kg bw) inhibited metastasis and potentiated the effect of oxaliplatin by reducing the expression of proliferating cell nuclear antigen. Liver metastatic nodules were reduced from 28 (PBS) to 14 (lunasin, P = 0.047) while combination of lunasin and oxaliplatin to 5 (P = 0.004). The tumor burden was reduced from 0.13 (PBS) to 0.10 (lunasin, P = 0.039) to 0.04 (lunasin + oxaliplatin, P < 0.0001). Moreover, lunasin potentiated the effect of oxaliplatin in modifying expression of proteins involved in apoptosis and metastasis including Bax, Bcl-2, IKK-α and p-p65. Lunasin inhibited metastasis of human colon cancer cells by direct binding with α5β1 integrin suppressing FAK/ERK/NF-κB signaling, and potentiated the effect of oxaliplatin in preventing the outgrowth of metastasis.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Colonic Neoplasms / drug therapy*
  • Colonic Neoplasms / metabolism
  • Colonic Neoplasms / pathology*
  • Extracellular Signal-Regulated MAP Kinases
  • Focal Adhesion Kinase 1 / metabolism
  • Humans
  • I-kappa B Kinase / metabolism
  • Integrin alpha5beta1 / metabolism*
  • Liver Neoplasms / drug therapy
  • Liver Neoplasms / pathology
  • Liver Neoplasms / secondary
  • Male
  • Mice
  • Mice, Nude
  • NF-kappa B / metabolism
  • NF-kappa B p50 Subunit / antagonists & inhibitors
  • Organoplatinum Compounds / administration & dosage
  • Organoplatinum Compounds / pharmacology*
  • Oxaliplatin
  • Proliferating Cell Nuclear Antigen / metabolism
  • Signal Transduction / drug effects
  • Soybean Proteins / administration & dosage
  • Soybean Proteins / metabolism*
  • Soybean Proteins / pharmacology*
  • bcl-2-Associated X Protein / metabolism

Substances

  • Antineoplastic Agents
  • GM2S-1 protein, Glycine max
  • Integrin alpha5beta1
  • NF-kappa B
  • NF-kappa B p50 Subunit
  • Organoplatinum Compounds
  • Proliferating Cell Nuclear Antigen
  • Soybean Proteins
  • bcl-2-Associated X Protein
  • Oxaliplatin
  • Focal Adhesion Kinase 1
  • PTK2 protein, human
  • I-kappa B Kinase
  • Extracellular Signal-Regulated MAP Kinases