c-Abl and Arg induce cathepsin-mediated lysosomal degradation of the NM23-H1 metastasis suppressor in invasive cancer.
c-Abl and Arg induce cathepsin-mediated lysosomal degradation of the NM23-H1 metastasis suppressor in invasive cancer.
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作者：
转移抑制因子包括一类不断增长的基因，其下调触发转移进展。与肿瘤抑制因子相反，转移抑制因子很少突变或缺失，关于其表达下调的机制知之甚少。在这里，我们证明了转移抑制因子NM 23-H1被溶酶体半胱氨酸组织蛋白酶（L，B）降解，其直接切割NM 23-H1。此外，c-Abl和Arg癌蛋白的活化通过增加半胱氨酸组织蛋白酶的转录和活化来诱导侵袭性癌细胞中的NM 23-H1降解。此外，c-Abl通过促进内体成熟来激活组织蛋白酶，这促进了匪23-H1运输到溶酶体，在溶酶体中匪23-H1被降解。重要的是，c-Abl/Arg的侵袭和转移促进活性依赖于它们诱导NM 23-H1降解的能力，并且该途径是临床相关的，因为c-Abl/Arg活性和NM 23-H1表达在原发性乳腺癌和黑色素瘤中呈负相关。因此，我们证明了一种新的机制，组织蛋白酶的表达上调癌细胞（通过Abl激酶）。我们还确定了细胞内组织蛋白酶在侵袭和转移中的新作用（转移抑制因子的降解）。最后，我们确定了致癌途径和转移抑制途径之间的新型串扰，从而提供了对NM 23-H1丢失过程的机制见解，这可能为恢复NM 23-H1表达和阻断转移进展的新策略铺平道路。
Metastasis suppressors comprise a growing class of genes whose downregulation triggers metastatic progression. In contrast to tumor suppressors, metastasis suppressors are rarely mutated or deleted, and little is known regarding the mechanisms by which their expression is downregulated. Here, we demonstrate that the metastasis suppressor, NM23-H1, is degraded by lysosomal cysteine cathepsins (L,B), which directly cleave NM23-H1. In addition, activation of c-Abl and Arg oncoproteins induces NM23-H1 degradation in invasive cancer cells by increasing cysteine cathepsin transcription and activation. Moreover, c-Abl activates cathepsins by promoting endosome maturation, which facilitates trafficking of NM23-H1 to the lysosome where it is degraded. Importantly, the invasion- and metastasis-promoting activity of c-Abl/Arg is dependent on their ability to induce NM23-H1 degradation, and the pathway is clinically relevant as c-Abl/Arg activity and NM23-H1 expression are inversely correlated in primary breast cancers and melanomas. Thus, we demonstrate a novel mechanism by which cathepsin expression is upregulated in cancer cells (via Abl kinases). We also identify a novel role for intracellular cathepsins in invasion and metastasis (degradation of a metastasis suppressor). Finally, we identify novel crosstalk between oncogenic and metastasis suppressor pathways, thereby providing mechanistic insight into the process of NM23-H1 loss, which may pave the way for new strategies to restore NM23-H1 expression and block metastatic progression.
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dictyostelium Discoideum核苷双磷酸激酶C在吞噬作用，大细胞增多症和胞吐作用中起负调节作用。
影响因子：
3.7
作者：
Annesley SJ;Bago R;Bosnar MH;Filic V;Marinović M;Weber I;Mehta A;Fisher PR
通讯作者：
Fisher PR
DOI：
10.3791/192
发表时间：
2007-01-01
期刊：
Journal of visualized experiments : JoVE
影响因子：
--
作者：
Fenyo, David;Wang, Qingjun;Chait, Brian T
通讯作者：
Chait, Brian T
影响因子：
4.8
作者：
Allington, Tressa M.;Galliher-Beckley, Amy J.;Schiemann, William P.
通讯作者：
Schiemann, William P.
影响因子：
0.7
作者：
De Wever, Olivier;Hendrix, An;Bracke, Marc
通讯作者：
Bracke, Marc
影响因子：
4.8
作者：
Jacob, Michele;Todd, Leslie A.;Pure, Ellen
通讯作者：
Pure, Ellen