P53- and mevalonate pathway-driven malignancies require Arf6 for metastasis and drug resistance.
P53- and mevalonate pathway-driven malignancies require Arf6 for metastasis and drug resistance.
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DOI：
10.1083/jcb.201510002
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发表时间：
2016-04-11
期刊：
影响因子：
--
通讯作者：
Sabe H
中科院分区：
文献类型：
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作者：
Hashimoto A;Oikawa T;Hashimoto S;Sugino H;Yoshikawa A;Otsuka Y;Handa H;Onodera Y;Nam JM;Oneyama C;Okada M;Fukuda M;Sabe H
甲羟戊酸途径（MVP）是一种与肿瘤侵袭性相关的代谢途径，已知与前酰化蛋白相关，但哪些前酰化蛋白对MVP驱动的癌症至关重要尚不清楚。Hashimoto等人表明，MVP驱动的癌症需要激活GTPase Arf6进行侵袭，而激活Arf6需要MVP底物Rab11。耐药、转移和间质转录程序是侵袭性乳腺肿瘤的主要特征。GTPase Arf6在肿瘤中经常过度表达，对促进上皮-间质转化和侵袭性至关重要。代谢甲羟戊酸途径（MVP）与肿瘤侵袭性有关，并且已知有戊酰化蛋白，但哪些戊酰化蛋白对MVP驱动的癌症至关重要尚不清楚。我们在这里表明，MVP需要依赖arf6的间质程序。MVP酶geranylgeranyl transferase II （GGT-II）及其底物Rab11b对于Arf6转运到质膜至关重要，在质膜上它被受体酪氨酸激酶激活。一致地，突变型p53，已知通过MVP支持肿瘤发生，通过GGT-II和Rab11b促进Arf6激活。抑制MVP和GGT-II阻断了癌细胞的侵袭和转移，降低了癌细胞对化疗药物的耐药性，但仅限于过表达Arf6和间充质程序组分的细胞。Arf6和间充质蛋白的过表达以及MVP活性的增强与患者生存不良相关。这些结果为mvp驱动的恶性肿瘤的分子基础提供了见解。
The mevalonate pathway (MVP) is a metabolic pathway associated with tumor invasiveness and is known to prenylate proteins, but which prenylated proteins are critical for MVP-driven cancers is unknown. Hashimoto et al. show that MVP-driven cancers require activation of the GTPase Arf6 for invasion and that the MVP substrate Rab11 is required for Arf6 activation. Drug resistance, metastasis, and a mesenchymal transcriptional program are central features of aggressive breast tumors. The GTPase Arf6, often overexpressed in tumors, is critical to promote epithelial–mesenchymal transition and invasiveness. The metabolic mevalonate pathway (MVP) is associated with tumor invasiveness and known to prenylate proteins, but which prenylated proteins are critical for MVP-driven cancers is unknown. We show here that MVP requires the Arf6-dependent mesenchymal program. The MVP enzyme geranylgeranyl transferase II (GGT-II) and its substrate Rab11b are critical for Arf6 trafficking to the plasma membrane, where it is activated by receptor tyrosine kinases. Consistently, mutant p53, which is known to support tumorigenesis via MVP, promotes Arf6 activation via GGT-II and Rab11b. Inhibition of MVP and GGT-II blocked invasion and metastasis and reduced cancer cell resistance against chemotherapy agents, but only in cells overexpressing Arf6 and components of the mesenchymal program. Overexpression of Arf6 and mesenchymal proteins as well as enhanced MVP activity correlated with poor patient survival. These results provide insights into the molecular basis of MVP-driven malignancy.