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A regulatory mechanism for RSK2 NH(2)-terminal kinase activity

Yong-Yeon Cho1, Ke Yao, Angelo Pugliese

  • 1The Hormel Institute, University of Minnesota, Austin, MN 55912, USA.

Cancer Research
|May 14, 2009
PubMed

Insights

Kaempferol, a natural compound, inhibits RSK2 (ribosomal S6 kinase 2) by binding to its NH(2)-terminal kinase domain. This inhibition is crucial for targeting RSK2 in cancer prevention and treatment.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Ribosomal S6 kinase 2 (RSK2) is critical for cell proliferation and transformation induced by tumor promoters.
  • Kaempferol, a natural compound, selectively inhibits RSK2 activity, but its molecular mechanism is unclear.

Purpose of the Study:

  • To elucidate the molecular mechanism of RSK2 activation and kaempferol's inhibitory action.
  • To investigate the role of RSK2 in cancer and the potential of kaempferol as a chemopreventive or chemotherapeutic agent.

Main Methods:

  • Investigated RSK2 activation via its NH(2)-terminal kinase domain (NTD) and COOH-terminal kinase domain (CTD).
  • Utilized homology modeling and small-molecule docking to identify kaempferol binding sites on RSK2.
  • Validated findings through mutagenesis experiments, immunohistofluorescence, and Western blot analysis.
  • Assessed kaempferol's effect on cancer cell proliferation.

Main Results:

  • RSK2 NTD activation is essential for CTD activation.
  • Kaempferol binds to the RSK2 NTD, specifically at amino acids Val(82) and Lys(100).
  • RSK2 protein levels are significantly elevated in cancer cells and tissues.
  • Kaempferol inhibited the proliferation of multiple human cancer cell lines.

Conclusions:

  • Kaempferol's selective binding to the RSK2 NTD provides a molecular basis for its inhibitory activity.
  • Targeting RSK2 with kaempferol presents a promising strategy for cancer chemoprevention and chemotherapy.

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