Chemosensitization by erythropoietin through inhibition of the NF-κB rescue pathway

被引:40
作者
Carvalho, G
Lefaucheur, C
Cherbonnier, C
Métivier, D
Chapel, A
Pallardy, M
Bourgeade, MF
Charpentier, B
Hirsch, F
Kroemer, G
机构
[1] Inst Gustave Roussy, CNRS, UMR8125, F-94805 Villejuif, France
[2] Univ Paris 11, Hop Paul Brousse, INSERM, U542, F-94802 Villejuif, France
[3] IRSN, Fontenay Aux Roses, France
[4] Fac Pharm Paris, INSERM, U461, F-92296 Chatenay Malabry, France
关键词
apoptosis; renal carcinoma; jak; leukemia;
D O I
10.1038/sj.onc.1208205
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Two cell lines that exemplify erythropoietin (EPO) receptor-positive tumors, human renal carcinoma cell lines RCC and the myelomonocytic leukemia cell line U937, were investigated for the apoptosis-modulatory potential of EPO. Cells cultured in the presence of EPO exhibited an elevated apoptotic response to cancer chemotherapeutic agents such as daunorubicin (Dauno) and vinblastine (VBL). Chemosensitization by EPO did not involve an increase in p53 activation, yet correlated with enhanced Bax/Bak-dependent mitochondrial membrane perturbation and caspase maturation. In vitro monotherapy with Dauno or VBL induced the degradation of IkappaBalpha, provoked the translocation of NF-kappaB p65/50 to the nucleus and stimulated the expression of an NF-kappaB-activatable reporter gene. All these signs of NF-kappaB activation were perturbed in the presence of EPO. Inhibition of JAK2, one of the receptor-proximal elements of EPO-mediated signal transduction, greatly diminished the EPO-mediated chemosensitization and NF-kappaB inhibition. EPO lost its death-facilitating effects in the presence of an NF-kappaB inhibitor, underscoring the cause-effect relationship between EPO-mediated chemosensitization and NF-kappaB inhibition. Altogether, these results suggest that, at least in a specific subset of tumors, EPO receptor agonists can prevent activation of the NF-kappaB pathway, thereby enhancing the propensity of EPO receptor-positive tumor cells to undergo apoptosis.
引用
收藏
页码:737 / 745
页数:9
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