P53- and Mevalonate Pathway–Driven Malignancies Require Arf6 for Metastasis and Drug Resistance

October 19, 2016

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.

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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:
P53- and Mevalonate Pathway–Driven Malignancies Require Arf6 for Metastasis and Drug Resistance

J. Cell Biol. Vol. 213 (1): 81-95. DOI: 10.1083/jcb.201510002

Watch the video in "Figures & Data" aquired with HyVolution super-resolution: Colocalization of Rab11b with Arf6 during the TGFβ1-induced PM recruitment of Arf6. Time-lapse recording was performed in MDA-MB-231 cells expressing Arf6-EGFP (green) and RFP-Rab11b (red), of which representative images are shown in Fig. S3 D. Frames were taken every 20 s for 20 min in total.


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