title: P53- and mevalonate pathway-driven malignancies require Arf6 for metastasis and drug resistance.
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.
authors.affiliation: Department of Molecular Biology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan.
authors.forename: Ari
authors.initials: A
authors.lastname: Hashimoto
authors.affiliation: Department of Molecular Biology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan.
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Oikawa
authors.affiliation: Department of Molecular Biology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Hashimoto
authors.affiliation: Department of Molecular Biology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Sugino
authors.affiliation: Department of Molecular Biology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan.
authors.forename: Ayumu
authors.initials: A
authors.lastname: Yoshikawa
authors.affiliation: Department of Molecular Biology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan.
authors.forename: Yutaro
authors.initials: Y
authors.lastname: Otsuka
authors.affiliation: Department of Molecular Biology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan.
authors.forename: Haruka
authors.initials: H
authors.lastname: Handa
authors.affiliation: Department of Molecular Biology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan.
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Onodera
authors.affiliation: Global Institution for Collaborative Research and Education, Hokkaido University, Sapporo 060-8638, Japan.
authors.forename: Jin-Min
authors.initials: JM
authors.lastname: Nam
authors.affiliation: Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan.
authors.forename: Chitose
authors.initials: C
authors.lastname: Oneyama
authors.affiliation: Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Okada
authors.affiliation: Department of Developmental Biology and Neurosciences, Graduate School of Life Sciences, Tohoku University, Sendai 980-8578, Japan.
authors.forename: Mitsunori
authors.initials: M
authors.lastname: Fukuda
authors.affiliation: Department of Molecular Biology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan sabeh@med.hokudai.ac.jp.
authors.forename: Hisataka
authors.initials: H
authors.lastname: Sabe
mesh_terms: D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D061986:MCF-7 Cells; D008798:Mevalonic Acid / Q000378:metabolism*; D009361:Neoplasm Invasiveness / Q000473:pathology; D009362:Neoplasm Metastasis / Q000473:pathology*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D005723:gamma-Glutamyltransferase / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000378:metabolism; D000099193:rab11 GTP-Binding Proteins
chemical_list: D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors; D000970:Antineoplastic Agents; D008798:Mevalonic Acid; D020794:Receptor Protein-Tyrosine Kinases; D016159:Tumor Suppressor Protein p53; D005723:gamma-Glutamyltransferase; D020691:rab GTP-Binding Proteins; D000099193:rab11 GTP-Binding Proteins; C495901:TP53 protein, human; C000715348:ARF6 protein, human