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Notch inhibition in Kaposi's sarcoma tumor cells leads to mitotic catastrophe through nuclear factor-kappaB signaling

Christine L Curry1, Laura L Reed, Eugenia Broude

  • 1Department of Pathology, Cardinal Bernardin Cancer Center, Loyola University Chicago, 2160 South First Avenue, Maywood, IL 60153, USA.

Molecular Cancer Therapeutics
|July 3, 2007
PubMed

Insights

Notch signaling inhibition in Kaposi's sarcoma (KS) cells causes cell cycle arrest and mitotic catastrophe. This process involves increased nuclear factor-kappaB (NF-kappaB) and cyclin B1, leading to KS tumor cell death.

Area of Science:

  • Oncology
  • Cell Biology
  • Molecular Biology

Background:

  • Kaposi's sarcoma (KS) is a prevalent cancer in AIDS patients, often linked to constitutively active Notch signaling in tumor cells.
  • Previous studies indicated Notch signaling blockade induces apoptosis in KS cells, preceded by G(2)-M cell cycle arrest, suggesting mitotic catastrophe.

Purpose of the Study:

  • To investigate the mechanism by which Notch inhibition leads to cell death in Kaposi's sarcoma.
  • To determine the role of cell cycle regulation and specific molecular pathways in Notch-inhibited KS cells.

Main Methods:

  • Utilized gamma-secretase inhibitors and Notch-1 small interfering RNA to block Notch signaling in KS tumor cells.
  • Analyzed cell cycle progression, mitotic index, and the presence of micronucleated cells.
  • Assessed the expression and localization of cyclin B1 and nuclear factor-kappaB (NF-kappaB) activity.

Main Results:

  • Notch inhibition induced G(2)-M cell cycle arrest and mitotic catastrophe, evidenced by micronucleation and elevated mitotic index.
  • Sustained increase in nuclear cyclin B1 was observed following Notch inhibition.
  • Increased nuclear factor-kappaB (NF-kappaB) activity was identified as a key mediator, contributing to cyclin B1 induction and G(2)-M arrest.

Conclusions:

  • Notch inhibition triggers mitotic catastrophe in Kaposi's sarcoma cells through a pathway involving NF-kappaB activation.
  • This aberrant mitosis is characterized by inappropriate cyclin B1 upregulation, ultimately leading to cell death.
  • Targeting Notch signaling presents a potential therapeutic strategy for Kaposi's sarcoma by inducing mitotic catastrophe.

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