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Protein kinase C-eta regulates Mcl-1 level via ERK1

Deepanwita Pal1, Alakananda Basu1

  • 1Institute for Molecular Medicine, University of North Texas Health Science Center, Fort Worth, TX, USA.

Cellular Signalling
|September 24, 2017
PubMed

Insights

Protein kinase C-eta (PKCη) overexpression in breast cancer promotes cell survival. This study reveals PKCη protects Mcl-1 from proteasomal degradation via the ERK pathway, offering new therapeutic targets.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • Protein kinase C-eta (PKCη) is overexpressed in breast cancer, inhibiting apoptosis and conferring chemoresistance.
  • The anti-apoptotic protein myeloid cell leukemia-1 (Mcl-1) is crucial for breast cancer cell survival and chemoresistance.

Purpose of the Study:

  • To investigate the regulatory role of PKCη in Mcl-1 levels within breast cancer cells.
  • To elucidate the signaling pathway through which PKCη influences Mcl-1 stability.

Main Methods:

  • Silencing of PKCη in breast cancer cell lines (MCF-7, T47D).
  • Assessment of Mcl-1 protein and mRNA levels, proteasomal degradation using inhibitors (MG132, lactacystin), and Western blotting.
  • Analysis of the involvement of Mule (Mcl-1 ubiquitin ligase), Akt, GSK3-β, and ERK signaling pathways.

Main Results:

  • PKCη silencing led to decreased Mcl-1 protein levels, independent of MCL1 mRNA levels.
  • Mcl-1 downregulation was prevented by proteasomal inhibitors and Mule knockdown.
  • PKCη knockdown reduced ERK phosphorylation, and ERK1 knockdown decreased Mcl-1, with ERK1 overexpression restoring Mcl-1 levels.

Conclusions:

  • PKCη protects Mcl-1 from ubiquitin-mediated proteasomal degradation.
  • The ERK signaling pathway is essential for PKCη-mediated regulation of Mcl-1 stability.
  • Targeting the PKCη-ERK-Mcl-1 axis may represent a novel therapeutic strategy for breast cancer.
Keywords:
Bcl-2ERKMcl-1MulePKCη

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