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 language | English (US) |
|---|---|
| Pages (from-to) | 1983-1992 |
| Number of pages | 10 |
| Journal | Molecular Cancer Therapeutics |
| Volume | 6 |
| Issue number | 7 |
| DOIs | |
| State | Published - Jul 1 2007 |
| Externally published | Yes |
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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 journal › Article
}
TY - JOUR
T1 - Notch inhibition in Kaposi's sarcoma tumor cells leads to mitotic catastrophe through nuclear factor-κB signaling
AU - Curry, Christine
AU - Reed, Laura L.
AU - Broude, Eugenia
AU - Golde, Todd E.
AU - Miele, Lucio
AU - Foreman, Kimberly E.
PY - 2007/7/1
Y1 - 2007/7/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=34447320201&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=34447320201&partnerID=8YFLogxK
U2 - 10.1158/1535-7163.MCT-07-0093
DO - 10.1158/1535-7163.MCT-07-0093
M3 - Article
C2 - 17604336
AN - SCOPUS:34447320201
VL - 6
SP - 1983
EP - 1992
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
SN - 1535-7163
IS - 7
ER -