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Research Articles

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

¹ Department of Pathology and Oncology Institute, Cardinal Bernardin Cancer Center, and ² Department of Microbiology and Immunology, Loyola University Chicago, Maywood, Illinois; ³ Ordway Research Institute, Albany, New York; and ⁴ Department of Neuroscience, Mayo Clinic, Jacksonville, Florida

Requests for reprints: Kimberly E. Foreman, Room 235, Department of Pathology, Cardinal Bernardin Cancer Center, Loyola University Chicago, 2160 South First Avenue, Maywood, IL 60153. Phone: 708-327-3320; Fax: 708-327-2245. E-mail: kforema{at}lumc.edu

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 -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 -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-B (NF-B) 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-B activity that inappropriately increases cyclin B1 resulting in cell death via mitotic catastrophe. [Mol Cancer Ther 2007;6(7):1983–92]

Grant support: Public Health Service grant CA108450 (K.E. Foreman) from the National Cancer Institute and a Medical Student grant (C.L. Curry) from the American Skin Association.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

⁵ L. Miele, unpublished data.

Received 2/ 8/07; revised 4/16/07; accepted 5/25/07.