Carvalho Gabrielle, Lefaucheur Carmen, Cherbonnier Claire, Métivier Didier, Chapel Alain, Pallardy Marc, Bourgeade Marie-Françoise, Charpentier Bernard, Hirsch François, Kroemer Guido
INSERM-U542, Paris XI University, Hôpital Paul Brousse, 16 avenue Paul Vaillant Couturier, F-94802 Villejuif, France.
Oncogene. 2005 Jan 27;24(5):737-45. doi: 10.1038/sj.onc.1208205.
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.
研究了两种可作为促红细胞生成素（EPO）受体阳性肿瘤代表的细胞系，即人肾癌细胞系RCC和骨髓单核细胞白血病细胞系U937，以探讨EPO的凋亡调节潜力。在EPO存在下培养的细胞对柔红霉素（Dauno）和长春碱（VBL）等癌症化疗药物表现出更高的凋亡反应。EPO介导的化学增敏作用并不涉及p53激活的增加，但与Bax/Bak依赖性线粒体膜扰动增强和半胱天冬酶成熟相关。用Dauno或VBL进行体外单一疗法可诱导IkappaBalpha降解，促使NF-kappaB p65/50易位至细胞核，并刺激NF-kappaB可激活报告基因的表达。在EPO存在下，所有这些NF-kappaB激活的迹象均受到干扰。抑制JAK2（EPO介导的信号转导的受体近端元件之一）可大大降低EPO介导的化学增敏作用和NF-kappaB抑制作用。在NF-kappaB抑制剂存在下，EPO失去了其促进死亡的作用，这突出了EPO介导的化学增敏作用与NF-kappaB抑制作用之间的因果关系。总之，这些结果表明，至少在特定的肿瘤亚群中，EPO受体激动剂可阻止NF-kappaB途径的激活，从而增强EPO受体阳性肿瘤细胞发生凋亡的倾向。
