Leukemic cell-surface CD13/aminopeptidase N and resistance to apoptosis mediated by endothelial cells.

Abstract

BACKGROUND:

Attachment of leukemic cells to vascular endothelial cells induces the vascular endothelial cells to release endothelial cell-derived interleukin 8 (endothelial IL-8), which then induces leukemic cells to undergo apoptosis. NB4, a human promyelocytic leukemic cell line that expresses high levels of cell-surface CD13/aminopeptidase N, does not undergo endothelial IL-8-induced apoptosis. Consequently, we investigated the relationship between cell-surface aminopeptidase activity and endothelial IL-8 induction of apoptosis in various leukemic cell lines.

METHODS:

CD13/aminopeptidase N activity and IL-8-induced apoptosis were examined in leukemic cell lines. Endothelial IL-8-induced apoptosis was examined further in NB4 cells, K562 cells (human chronic myelogenous leukemic cells expressing low levels of CD13/aminopeptidase N), CD13/aminopeptidase N-transfected K562 (K562/CD13) cells that overexpress aminopeptidase, and mock-transfected K562 cells (vector only). These cells were also cocultured with a vascular endothelial cell layer to investigate the association between aminopeptidase activity and apoptosis in this system. All statistical tests were two-sided.

RESULTS:

Endothelial IL-8 induced apoptosis in K562 cells but not in K562/CD13 cells. A combination of an aminopeptidase inhibitor (such as bestatin) and endothelial IL-8 induced apoptosis in NB4 cells and K562/CD13 cells (2.88-fold difference [95% confidence interval [CI] = 1.82-fold to 3.94-fold], P =.004 for bestatin-treated NB4 cells and 4.31-fold difference [95% CI = 3.52-fold to 5.10-fold], P<.001 for bestatin-treated K562/CD13 cells). When aminopeptidase activity in NB4 cells was modulated by aminopeptidase inhibitors, a statistically significant correlation was found between aminopeptidase activity and the proportion of apoptotic cells induced by endothelial IL-8 (r = -.837, P<.001 by Pearson's correlation coefficient; r = -.697, P =.013 by Spearman's correlation analysis by ranks). K562/CD13 cells cocultured with vascular endothelial cells did not undergo apoptosis, but the addition of bestatin resulted in the induction of apoptosis in K562/CD13 cells (2.70-fold difference [95% CI = 1.77-fold to 3.63-fold], P<.001). Bestatin treatment increased the level of IL-8 mRNA in and the amount of IL-8 secreted by vascular endothelial cells.

CONCLUSIONS:

High levels of cell-surface CD13/aminopeptidase N appear to allow leukemic cells to resist endothelial IL-8-induced apoptosis. The combination of endothelial IL-8 and bestatin induce leukemic cells expressing high levels of CD13/aminopeptidase N to undergo apoptosis. Bestatin may be useful for treating patients with leukemia.

• Authors: Yuji Mishima, Yuko Matsumoto-Mishima, Yasuhito Terui, Misa Katsuyama, Muneo Yamada, Masaki Mori, Yukihito Ishizaka, Kazuma Ikeda, Jun-ichiro Watanabe, Nobuyuki Mizunuma, Hirotoshi Hayasawa, Kiyohiko Hatake
• Journal: Journal of the National Cancer Institute (J Natl Cancer Inst) Vol. 94 Issue 13 Pg. 1020-8 (Jul 03 2002) ISSN: 0027-8874 [Print] United States
• PMID: 12096087 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibiotics, Antineoplastic
• Interleukin-8
• CD13 Antigens
• Leucine
• ubenimex

Topics

• Antibiotics, Antineoplastic (pharmacology)
• Apoptosis (drug effects, physiology)
• Blotting, Northern
• CD13 Antigens (antagonists & inhibitors, genetics, metabolism)
• Cell Division (drug effects)
• Cells, Cultured
• Endothelium, Vascular (physiology)
• Fluorescent Antibody Technique
• Humans
• In Situ Nick-End Labeling
• Interleukin-8 (metabolism, pharmacology, physiology)
• K562 Cells (pathology)
• Leucine (analogs & derivatives, pharmacology)
• Leukemia (pathology)
• Transfection
• Umbilical Veins