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

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Title: P53-and mevalonate pathway-driven malignancies require Arf6 for metastasis and drug resistance
Authors: Hashimoto, Ari Browse this author →KAKEN DB
Oikawa, Tsukasa Browse this author →KAKEN DB
Hashimoto, Shigeru Browse this author →KAKEN DB
Sugino, Hirokazu Browse this author
Yoshikawa, Ayumu Browse this author
Otsuka, Yutaro Browse this author
Handa, Haruka Browse this author
Onodera, Yasuhito Browse this author →KAKEN DB
Nam, Jin-Min Browse this author
Oneyama, Chitose Browse this author →KAKEN DB
Okada, Masato Browse this author →KAKEN DB
Fukuda, Mitsunori Browse this author →KAKEN DB
Sabe, Hisataka Browse this author →KAKEN DB
Issue Date: 11-Apr-2016
Publisher: Rockefeller University Press
Journal Title: Journal of cell biology
Volume: 213
Issue: 1
Start Page: 81
End Page: 95
Publisher DOI: 10.1083/jcb.201510002
Abstract: 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.
Rights: © Hashimoto et al., 2016. Originally published in Journal of Cell Biology. doi:10.1083/jcb.201510002
Type: article
Appears in Collections:国際連携研究教育局 : GI-CoRE (Global Institution for Collaborative Research and Education : GI-CoRE) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)
医学院・医学研究院 (Graduate School of Medicine / Faculty of Medicine) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: 佐邊 壽孝

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