Taspase1 functions as a non-oncogene addiction protease that coordinates cancer cell proliferation and apoptosis.
Taspase1 functions as a non-oncogene addiction protease that coordinates cancer cell proliferation and apoptosis.
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DOI：
10.1158/0008-5472.can-10-0027
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发表时间：
2010-07-01
期刊：
影响因子：
11.2
通讯作者：
Hsieh JJ
中科院分区：
文献类型：
--
作者：
Chen DY;Liu H;Takeda S;Tu HC;Sasagawa S;Van Tine BA;Lu D;Cheng EH;Hsieh JJ
taspe1 (TASP-1)， MLL和TFIIAα-β切割蛋白酶，促进细胞增殖并允许致癌起始。在这里，我们证明了它在癌症维持中的关键作用，从而提供了一个新的抗癌靶点。Taspase1在原发性人类癌症中过表达，癌细胞缺乏Taspase1不仅会破坏增殖，还会促进细胞凋亡。机制上，Taspase1的缺失诱导CDKIs （p16、p21和p27）的水平，并降低抗凋亡MCL-1的水平。在治疗上，Taspase1的缺乏与化疗药物和ABT-737 （BCL-2/BCL-XL的抑制剂）协同作用，杀死癌细胞。Taspase1单独或与MYC、RAS或E1A联合不能分别转化NIH/3T3细胞或原代mef，但在癌症的发生和维持中发挥关键作用。因此，Taspase1被更好地归类为“非癌基因成瘾”蛋白酶，抑制它可能提供一种新的抗癌治疗策略。在肿瘤发生过程中，癌基因对次要非癌基因的依赖强调了“非癌基因依赖”假说，在该假说中，大量非癌基因起着维持癌症表型的作用，并提供了有吸引力的抗癌治疗靶点。针对癌症成瘾的非癌基因的成功癌症治疗药物的出现，支持了小分子Taspase1抑制剂在癌症治疗中的未来发展和潜在应用。
Taspase1 (TASP-1), the MLL and TFIIAα-β cleaving protease, enables cell proliferation and permits oncogenic initiation. Here, we demonstrate its critical role in cancer maintenance and thus offer a new anticancer target. Taspase1 is over-expressed in primary human cancers and deficiency of Taspase1 in cancer cells not only disrupts proliferation but also enhances apoptosis. Mechanistically, loss of Taspase1 induces the levels of CDKIs (p16, p21, and p27) and reduces the level of anti-apoptotic MCL-1. Therapeutically, deficiency of Taspase1 synergizes with chemotherapeutic agents and ABT-737, an inhibitor of BCL-2/BCL-XL, to kill cancer cells. Taspase1 alone or in conjunction with MYC, RAS, or E1A fail to transform NIH/3T3 cells or primary MEFs, respectively, and yet plays critical roles in cancer initiation and maintenance. Therefore, Taspase1 is better classified as a “non-oncogene addiction” protease, of which inhibition may offer a novel anticancer therapeutic strategy. The reliance of oncogenes on subordinate non-oncogenes during tumorigenesis underscores the “non-oncogene addiction” hypothesis in which a large class of non-oncogenes functions to maintain cancer phenotypes and presents attractive anti-cancer therapeutic targets. The emergence of successful cancer therapeutics targeting non-oncogenes to which cancers are addicted supports the future development and potential application of small molecule Taspase1 inhibitors for cancer therapy.