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

Christine Curry, Laura L. Reed, Eugenia Broude, Todd E. Golde, Lucio Miele, Kimberly E. Foreman

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Kaposi's sarcoma (KS) is the most common neoplasm in untreated AIDS patients and accounts for significant morbidity and mortality worldwide. We have recently reported that Notch signaling (which plays an important role in cell proliferation, apoptosis, and oncogenesis) is constitutively activated in KS tumor cells. Blockade of this activity using γ-secretase inhibitors resulted in apoptosis of SLK cells, a KS tumor cell line; however, this apoptosis was preceded by a prolonged G2-M cell cycle arrest. This result led us to hypothesize that the cells were undergoing mitotic catastrophe, an abnormal mitosis that leads to eventual cell death. Here, we show that Notch inhibition in KS tumor cells using γ-secretase inhibitors or Notch-1 small interfering RNA resulted in G2-M cell cycle arrest and mitotic catastrophe characterized by the presence of micronucleated cells and an increased mitotic index. Interestingly, Notch inhibition led to a sustained increase in nuclear cyclin B1, a novel observation suggesting that Notch signaling can modulate expression of this critical cell cycle protein. Further analysis showed the induction of cyclin B1 was due, at least in part, to increased nuclear factor-κB (NF-κB) activity, which was also required for the G2-M growth arrest after Notch inhibition. Taken together, these studies suggest that Notch inhibition can initiate aberrant mitosis by inducing NF-κB activity that inappropriately increases cyclin B1 resulting in cell death via mitotic catastrophe.

Original languageEnglish (US)
Pages (from-to)1983-1992
Number of pages10
JournalMolecular Cancer Therapeutics
Volume6
Issue number7
DOIs
StatePublished - Jul 1 2007
Externally publishedYes

Fingerprint

Kaposi's Sarcoma
Cyclin B1
G2 Phase Cell Cycle Checkpoints
Amyloid Precursor Protein Secretases
Neoplasms
Apoptosis
Mitosis
Cell Death
Cell Cycle Proteins
Mitotic Index
Tumor Cell Line
Small Interfering RNA
Carcinogenesis
Acquired Immunodeficiency Syndrome
Cell Proliferation
Observation
Morbidity
Mortality
Growth

ASJC Scopus subject areas

  • Oncology
  • Drug Discovery
  • Pharmacology

Cite this

Notch inhibition in Kaposi's sarcoma tumor cells leads to mitotic catastrophe through nuclear factor-κB signaling. / Curry, Christine; Reed, Laura L.; Broude, Eugenia; Golde, Todd E.; Miele, Lucio; Foreman, Kimberly E.

In: Molecular Cancer Therapeutics, Vol. 6, No. 7, 01.07.2007, p. 1983-1992.

Research output: Contribution to journalArticle

Curry, Christine ; Reed, Laura L. ; Broude, Eugenia ; Golde, Todd E. ; Miele, Lucio ; Foreman, Kimberly E. / Notch inhibition in Kaposi's sarcoma tumor cells leads to mitotic catastrophe through nuclear factor-κB signaling. In: Molecular Cancer Therapeutics. 2007 ; Vol. 6, No. 7. pp. 1983-1992.
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