Notch inhibition in Kaposi's sarcoma tumor cells leads to mitotic catastrophe through nuclear factor-kappaB signaling.
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 gamma-secretase inhibitors resulted in apoptosis of SLK cells, a KS tumor cell line; however, this apoptosis was preceded by a prolonged G(2)-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 gamma-secretase inhibitors or Notch-1 small interfering RNA resulted in G(2)-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-kappaB (NF-kappaB) activity, which was also required for the G(2)-M growth arrest after Notch inhibition. Taken together, these studies suggest that Notch inhibition can initiate aberrant mitosis by inducing NF-kappaB activity that inappropriately increases cyclin B1 resulting in cell death via mitotic catastrophe.
Curry
Christine L
CL
Department of Pathology, Cardinal Bernardin Cancer Center, Loyola University Chicago, 2160 South First Avenue, Maywood, IL 60153, USA.
Reed
Laura L
LL
Broude
Eugenia
E
Golde
Todd E
TE
Miele
Lucio
L
Foreman
Kimberly E
KE
D016203:CDC2 Protein Kinase / Q000378:metabolism; D002457:Cell Extracts; D045744:Cell Line, Tumor; D019926:Cyclin B / Q000378:metabolism; D056744:Cyclin B1; D004273:DNA, Neoplasm / Q000378:metabolism; D016195:G2 Phase; D017930:Genes, Reporter; D006801:Humans; D015162:Micronucleus Tests; D008938:Mitosis; D016328:NF-kappa B / Q000378:metabolism*; D021381:Protein Transport; D051880:Receptors, Notch / Q000037:antagonists & inhibitors*; D012514:Sarcoma, Kaposi / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D015398:Signal Transduction
C534699:CCNB1 protein, human; D002457:Cell Extracts; D019926:Cyclin B; D056744:Cyclin B1; D004273:DNA, Neoplasm; D016328:NF-kappa B; D051880:Receptors, Notch; D016203:CDC2 Protein Kinase