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

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

    Research output: Contribution to journalArticle

    34 Citations (Scopus)

    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.

    Original languageEnglish
    Pages (from-to)81-95
    Number of pages15
    JournalJournal of Cell Biology
    Volume213
    Issue number1
    DOIs
    Publication statusPublished - 2016 Apr 1

    ASJC Scopus subject areas

    • Cell Biology

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