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A feed-forward loop involving protein kinase Calpha and microRNAs regulates tumor cell cycle

Ezra E W Cohen1, Hongyan Zhu, Mark W Lingen

  • 1Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA.

Cancer Research
|January 2, 2009
PubMed

Insights

Protein kinase Calpha (PKCalpha) drives head and neck cancer by disrupting the cell cycle. Inhibiting PKCalpha reduces tumor growth by restoring cell cycle regulation and decreasing DNA synthesis.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Protein kinase Calpha (PKCalpha) is linked to cancer, but its precise role in head and neck squamous cell carcinoma (SCCHN) remains unclear.
  • Understanding the molecular mechanisms of PKCalpha in SCCHN is crucial for developing targeted therapies.

Purpose of the Study:

  • To elucidate the mechanism by which PKCalpha promotes SCCHN progression.
  • To investigate the role of PKCalpha in cell cycle regulation and DNA synthesis in SCCHN.
  • To evaluate PKCalpha as a potential therapeutic target for SCCHN.

Main Methods:

  • Utilized SCCHN cell lines and xenograft models to study PKCalpha function.
  • Assessed the impact of PKCalpha inhibition/depletion on cell proliferation, DNA synthesis, and cell cycle regulators.
  • Analyzed extracellular signal-regulated kinase (ERK) phosphorylation and cyclin E synthesis.
  • Investigated the regulation of microRNA-15a (miR-15a) by PKCalpha.
  • Correlated PKCalpha and cyclin E expression with miR-15a levels in primary tumors.

Main Results:

  • PKCalpha promotes SCCHN proliferation through a feed-forward network that deregulates the cell cycle.
  • PKCalpha inhibition decreased SCCHN cell proliferation and tumor growth in vivo.
  • PKCalpha suppression reduced DNA synthesis by inhibiting ERK phosphorylation and cyclin E production.
  • PKCalpha down-regulates miR-15a, a negative regulator of cyclin E and other cell cycle proteins.
  • Elevated PKCalpha and cyclin E expression, inversely correlated with miR-15a, were observed in primary SCCHN tumors.
  • High PKCalpha expression correlated with poor prognosis in SCCHN patients.

Conclusions:

  • PKCalpha is a key driver of SCCHN tumor growth via a mechanism involving ERK activation and miR-15a suppression.
  • This study identifies a novel PKCalpha-mediated feed-forward loop regulating cell cycle progression in SCCHN.
  • Targeting PKCalpha represents a promising therapeutic strategy for SCCHN, potentially by restoring cell cycle control.

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