Securinine induces p73-dependent apoptosis preferentially in p53-deficient colon cancer cells
Securinine induces p73-dependent apoptosis preferentially in p53-deficient colon cancer cells
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DOI：
10.1096/fj.09-148999
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发表时间：
2010-06-01
期刊：
影响因子：
4.8
通讯作者：
Wald, David N.
中科院分区：
文献类型：
--
作者：
Rana, Sonia;Gupta, Kalpana;Wald, David N.
发现在保护正常细胞的同时优先杀死癌细胞的药物，为克服许多现有化疗药物的毒性提供了可能性。由于P53在癌症中经常失活，因此优先杀死P53缺失细胞和保护野生型P53表达细胞的药物是非常理想的化疗药物。通过使用仅在P53表达上不同的两对等基因结肠癌细胞株(RKO和HCT116)，一叶绿碱被发现表现出这些特性。一叶绿碱(30 MU M)作用72 h后，可诱导73%的p53缺失的HCT116细胞(LD50为17.5 mU)发生凋亡，而HCT116亲代细胞的LD50为17.6%(LD50为50 mM)。一叶菜碱诱导P53基因缺陷细胞死亡的机制涉及P53家族成员p73的诱导。有趣的是，促凋亡蛋白p73在表达p53的结肠癌细胞中下调。这种以p53依赖的方式对p73的差异调控揭示了一种优先靶向癌细胞的新途径。与P53缺失的细胞不同，表达P53的细胞通过P53介导的p21上调来保护细胞免于死亡。-Rana，S.，Gupta，K.，Gomez，J.，Matsuyama，S.，Chakrabarti，A.，Agarwal，M.L.，Agarwal，A.，Agarwal，M.K.，Wald，D.N.一叶绿碱优先诱导p53缺失的结肠癌细胞依赖于p73的凋亡。FASE B J.24,2126-2134(2010)。Www.fasebj.org
The identification of agents that preferentially kill cancer cells while protecting normal cells offers the potential to overcome toxicities found in many existing chemotherapeutic agents. Because p53 is frequently inactivated in cancer, agents that preferentially kill p53-null cells and protect wild-type p53-expressing cells are highly desirable chemotherapeutic agents. By using pairs of isogenic colon cancer cell lines that differ only in p53 expression (RKO and HCT116), securinine was found to exhibit these properties. Securinine (30 mu M) induces apoptosis in 73% of p53-null HCT116 cells (LD50 17.5 mu M) as opposed to 17.6% of HCT116 parental cells (LD50 50 mu M) at 72 h after treatment. The mechanism of securinine-mediated death in p53-deficient cells involves the induction of the p53 family member, p73. Interestingly, the proapoptotic protein p73 is down-regulated in colon cancer cells expressing p53. This differential regulation of p73 in a p53-dependent fashion reveals a novel pathway for preferentially targeting cancer cells. In contrast to p53-deficient cells, cells expressing p53 are protected from cell death through the p53-mediated up-regulation of p21. These studies reveal a novel approach to specifically target colon cancer cells lacking p53 as well as identify a novel clinically relevant pathway to selectively induce p73 in p53-null cells.-Rana, S., Gupta, K., Gomez, J., Matsuyama, S., Chakrabarti, A., Agarwal, M. L., Agarwal, A., Agarwal, M. K., Wald, D. N. Securinine induces p73-dependent apoptosis preferentially in p53-deficient colon cancer cells. FASEB J. 24, 2126- 2134 (2010). www.fasebj.org