RKIP sensitizes prostate and breast cancer cells to drug-induced apoptosis
RKIP sensitizes prostate and breast cancer cells to drug-induced apoptosis
复制标题
DOI：
10.1074/jbc.m313816200
复制
发表时间：
2004-04-23
影响因子：
4.8
通讯作者：
Yeung, KC
中科院分区：
文献类型：
--
作者：
Chatterjee, D;Bai, Y;Yeung, KC
癌细胞比正常细胞更容易受到化疗药物诱导的细胞凋亡的影响。虽然已经证明敏感性的增加是由于癌症发展过程中癌蛋白的解除管制(Evan， G. I., and Vousden， K. H. (2001) Nature 411, 342-348；Green， D. R.和Evan， G. I. (2002) Cancer Cell 1, 19-30)，对导致癌细胞凋亡阈值变化的信号通路知之甚少。本研究表明，在致瘤性前列腺癌和乳腺癌细胞中，RKIP的低表达水平在化疗药物治疗后被迅速诱导，使细胞对凋亡敏感。我们发现RKIP的最大表达与细胞凋亡的发生完全相关。在耐dna损伤剂的癌细胞中，用这些药物治疗不会上调RKIP的表达。然而，RKIP的异位表达使dna损伤剂抗性细胞发生凋亡。这种致敏可以通过上调生存途径来逆转。通过表达反义和小干扰RNA （siRNA）下调内源性RKIP，使敏感癌细胞对抗癌药物诱导的凋亡具有抗性。我们的研究表明，RKIP可能是导致细胞凋亡的信号转导通路的新效应物，也是临床相关化疗药物治疗后人类癌细胞和肿瘤发病机制的预后标志物。
Cancer cells are more susceptible to chemotherapeutic agent-induced apoptosis than their normal counterparts. Although it has been demonstrated that the increased sensitivity results from deregulation of oncoproteins during cancer development (Evan, G. I., and Vousden, K. H. (2001) Nature 411, 342-348; Green, D. R., and Evan, G. I. (2002) Cancer Cell 1, 19-30), little is known about the signaling pathways leading to changes in the apoptotic threshold in cancer cells. Here we show that low RKIP expression levels in tumorigenic human prostate and breast cancer cells are rapidly induced upon chemotherapeutic drug treatment, sensitizing the cells to apoptosis. We show that the maximal RKIP expression correlates perfectly with the onset of apoptosis. In cancer cells resistant to DNA-damaging agents, treatment with the drugs does not up-regulate RKIP expression. However, ectopic expression of RKIP resensitizes DNA-damaging agent-resistant cells to undergo apoptosis. This sensitization can be reversed by up-regulation of survival pathways. Down-regulation of endogenous RKIP by expression of antisense and small interfering RNA (siRNA) confers resistance on sensitive cancer cells to anticancer drug-induced apoptosis. Our studies suggest that RKIP may represent a novel effector of signal transduction pathways leading to apoptosis and a prognostic marker of the pathogenesis of human cancer cells and tumors after treatment with clinically relevant chemotherapeutic drugs.