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Cocoa procyanidins suppress transformation by inhibiting mitogen-activated protein kinase kinase

Nam Joo Kang1, Ki Won Lee, Dong Eun Lee

  • 1Hormel Institute, University of Minnesota, 801 16th Avenue NE, Austin, MN 55912, USA.

The Journal of Biological Chemistry
|June 4, 2008
PubMed

Insights

Cocoa procyanidins, potent antioxidants, inhibit cancer cell transformation by blocking MEK kinase activity. This discovery reveals a key mechanism behind cocoa's chemopreventive potential.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Cocoa exhibits chemopreventive properties against chemically induced carcinogenesis and possesses antioxidant activity in humans.
  • The precise molecular mechanisms underlying cocoa's cancer-preventive effects and the roles of its active compounds remain largely unelucidated.

Purpose of the Study:

  • To investigate the molecular mechanisms by which cocoa procyanidins exert their chemopreventive effects.
  • To determine if cocoa compounds can inhibit neoplastic cell transformation and identify the specific molecular targets involved.

Main Methods:

  • Utilized JB6 P+ mouse epidermal cells to assess neoplastic cell transformation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA).
  • Evaluated the inhibitory effects of cocoa procyanidin fraction (CPF) and procyanidin B2 on TPA-induced transformation, cyclooxygenase-2 expression, activator protein-1 (AP-1) and nuclear factor-kappaB (NF-κB) activation.
  • Assessed the impact of cocoa compounds on the phosphorylation of MEK, ERK, and RSK signaling pathways using in vitro and ex vivo kinase assays.
  • Investigated the direct binding of CPF and procyanidin B2 to MEK1 and their effects on MEK/ERK pathway activation induced by epidermal growth factor (EGF) or H-Ras.

Main Results:

  • CPF and procyanidin B2 significantly inhibited TPA-induced neoplastic transformation in JB6 P+ cells in a dose-dependent manner.
  • These cocoa compounds suppressed TPA-induced cyclooxygenase-2 expression, AP-1 and NF-κB activation, and the phosphorylation of MEK, ERK, and RSK.
  • In vitro and ex vivo assays confirmed that CPF and procyanidin B2 directly inhibit MEK1 kinase activity and bind to MEK1.
  • Procyanidin B2 demonstrated stronger inhibition of MEK1 activity and neoplastic cell transformation compared to the known MEK inhibitor PD098059.
  • Theobromine, another cocoa component, showed no significant effect on the studied transformation pathways.

Conclusions:

  • Cocoa procyanidins, particularly procyanidin B2, effectively inhibit neoplastic cell transformation by suppressing the MEK/ERK signaling pathway.
  • These findings elucidate a key molecular mechanism for cocoa's chemopreventive potential, highlighting MEK kinase as a critical target.
  • Cocoa procyanidins represent promising natural compounds for cancer prevention strategies targeting the MEK pathway.

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