P53-and mevalonate pathway-driven malignancies require Arf6 for metastasis and drug resistance

Hashimoto Ari; Oikawa Tsukasa; Hashimoto Shigeru; Sugino Hirokazu; Yoshikawa Ayumu; Otsuka Yutaro; Handa Haruka; Onodera Yasuhito; Nam Jin-Min; Oneyama Chitose; Okada Masato; Fukuda Mitsunori; Sabe Hisataka

タイトル	en P53-and mevalonate pathway-driven malignancies require Arf6 for metastasis and drug resistance
作成者	en Hashimoto, Ari NRID 1000060390803 en Oikawa, Tsukasa NRID 1000020457055 en Hashimoto, Shigeru NRID 1000050311303 en Sugino, Hirokazu en Yoshikawa, Ayumu en Otsuka, Yutaro en Handa, Haruka en Onodera, Yasuhito NRID 1000090435561 en Nam, Jin-Min en Oneyama, Chitose NRID 1000090373208 en Okada, Masato NRID 1000010177058 en Fukuda, Mitsunori NRID 1000050311361 en Sabe, Hisataka NRID 1000040187282
アクセス権	open access
権利情報	en © Hashimoto et al., 2016. Originally published in Journal of Cell Biology. doi:10.1083/jcb.201510002 http://creativecommons.org/licenses/by-nc-sa/3.0/ en Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported
主題	NDC 490
内容注記	Abstract en 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.
出版者	en Rockefeller University Press
日付	Issued2016-04-11
言語	eng
資源タイプ	journal article
出版タイプ	VoR
資源識別子	HDL http://hdl.handle.net/2115/62128
関連	isIdenticalTo DOI https://doi.org/10.1083/jcb.201510002
収録誌情報	PISSN 0021-9525 NCID AA00694812 en Journal of cell biology 巻213 号1 開始ページ81 終了ページ95
ファイル	fulltext JCB-2016-Hashimoto-81-95.pdf 3.12 MB (application/pdf) Issued2016-04-11 fulltext JCB_201510002_V1.mp4 1.99 MB (video/mp4) Issued2016-04-11 fulltext JCB_201510002_sm.pdf 1.77 MB (application/pdf) Issued2016-04-11
コンテンツ更新日時	2023-07-26