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p90 RSK2 mediates antianoikis signals by both transcription-dependent and -independent mechanisms

Lingtao Jin1, Dan Li, Jong Seok Lee

  • 1Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, USA.

Molecular and Cellular Biology
|April 24, 2013
PubMed

Insights

Ribosomal S6 kinase 2 (RSK2) promotes cancer cell invasion and metastasis by preventing anoikis, a form of apoptosis. Inhibiting RSK2 sensitizes tumor cells to anoikis through ASK1 and CREB signaling pathways.

Area of Science:

  • Cell Biology
  • Molecular Oncology
  • Cancer Research

Background:

  • Anoikis, a form of apoptosis, is crucial for preventing tumor cell survival and metastasis.
  • Mechanisms by which invasive and metastatic cancer cells evade anoikis are not fully understood.

Purpose of the Study:

  • To investigate the role of Ribosomal S6 kinase 2 (RSK2) in anoikis evasion in cancer cells.
  • To elucidate the signaling pathways through which RSK2 mediates anoikis resistance.

Main Methods:

  • Knockdown of RSK2 in diverse cancer cell lines.
  • Analysis of phosphorylation targets including apoptosis signal-regulating kinase 1 (ASK1) and cyclic AMP (cAMP) response element-binding protein (CREB).
  • Investigated RSK2-mediated inhibition of ASK1 activity and regulation of gene expression via CREB.

Main Results:

  • RSK2 knockdown sensitized cancer cells to anoikis induction.
  • RSK2 inhibits ASK1 via phosphorylation at S83, T1109, and T1326, affecting ATP binding and substrate interaction.
  • RSK2 signaling through CREB regulates expression of antiapoptotic (PTK6) and proapoptotic (ING3) factors, conferring anoikis protection.
  • Combined knockdown of ASK1, PTK6 overexpression, or ING3 knockdown rescued anoikis sensitivity in RSK2-deficient cells.

Conclusions:

  • RSK2 acts as a signal integrator, providing transcription-independent and -dependent anoikis protection to cancer cells.
  • RSK2 signaling through ASK1 and CREB pathways contributes to cancer cell invasion and tumor metastasis.
  • Targeting RSK2 may represent a therapeutic strategy to overcome anoikis resistance in cancer.

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