Elsevier

Neoplasia

Volume 10, Issue 12, December 2008, Pages 1402-1410
Neoplasia

Resistance to Cytarabine Induces the Up-regulation of NKG2D Ligands and Enhances Natural Killer Cell Lysis of Leukemic Cells1

https://doi.org/10.1593/neo.08972Get rights and content
Under a Creative Commons license
open access

Prolonged treatment of leukemic cells with chemotherapeutic agents frequently results in development of drug resistance. Moreover, selection of drug-resistant cell populations may be associated with changes in malignant properties such as proliferation rate, invasiveness, and immunogenicity. In the present study, the sensitivity of cytarabine (1-β-d-arabinofuranosylcytosine, araC)-resistant and parental human leukemic cell lines (T-lymphoid H9 and acute T-lymphoblastic leukemia Molt-4) to natural killer (NK) cell-mediated killing was investigated. The results obtained demonstrate that araC-resistant H9 and Molt-4 (H9rARAC100 and Molt-4rARAC100) cell lines are more sensitive to NK cell-mediated lysis than their respective parental cell lines. This increased sensitivity was associated with a higher surface expression of ligands for the NK cell-activating receptor NKG2D, notably UL16 binding protein-2 (ULBP-2) and ULBP-3 in H9rARAC100 and Molt-4rARAC100 cell lines. Blocking ULBP-2 and ULBP-3 or NKG2D with monoclonal antibody completely abrogated NK cell lysis. Constitutive phosphorylated extracellular signal-regulated kinase (ERK) but not pAKT was higher in araC-resistant cells than in parental cell lines. Inhibition of ERK using ERK inhibitor PD98059 decreased both ULBP-2/ULBP-3 expression and NK cell cytotoxicity. Furthermore, overexpression of constitutively active ERK in H9 parental cells resulted in increased ULBP-2/ULBP-3 expression and enhanced NK cell lysis. These results demonstrate that increased sensitivity of araC-resistant leukemic cells to NK cell lysis is caused by higher NKG2D ligand expression, resulting from more active ERK signaling pathway.

Abbreviations

AraC
cytarabine
E/T
effector-target
ERK
extracellular signal-regulated kinase
G3PDH
glyceraldehyde-3-phosphate dehydrogenase
IL-2
interleukin-2
IMDM
Iscove's modified Dulbecco's medium
MHC-I
major histocompatibility complex class I
MICA/B
MHC-I-related chain A/B
NK
natural killer
NKG2D
natural killer group 2D
ULBP
UL-16 binding protein

Cited by (0)

1

The authors gratefully acknowledge the support by the organization “Hilfe für krebskranke Kinder, Frankfurt/Main e.V.,” by the foundation “Frankfurter Stiftung für krebskranke Kinder,” and by the European Commission-funded Co-operative Research and Specific Targeted Research Projects: COOP-CT-2004, contract no. 512864 and LSHB-CT-2004, contract no. 512054 respectively.