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Open AccessArticle

N6-Isopentenyladenosine Inhibits Colorectal Cancer and Improves Sensitivity to 5-Fluorouracil Targeting FBXW7 Tumor Suppressor

1
Department of Pharmacy, University of Salerno, 84084 Fisciano (SA), Italy
2
PhD Program in Drug Discovery and Development, University of Salerno, Via Giovanni Paolo II 132, 84084 Fisciano (SA), Italy
3
Department of Medicine, Surgery and Dentistry, University of Salerno, 84081 Baronissi (Salerno), Italy
4
Department of Molecular Medicine and Medical Biotechnologies, University of Naples “Federico II”, 80131 Naples, Italy
5
Institute of Endocrinology and Experimental Oncology “Gaetano Salvatore” (IEOS), National Research Council (CNR), 80131 Naples, Italy
*
Author to whom correspondence should be addressed.
D.F. and C.P. share equal contribution.
P.G. and M.B. share equal senior authorship.
Cancers 2019, 11(10), 1456; https://doi.org/10.3390/cancers11101456
Received: 20 July 2019 / Revised: 20 September 2019 / Accepted: 25 September 2019 / Published: 28 September 2019
N6-isopentenyladenosine has been shown to exert potent in vitro antitumor activity on different human cancers, including colorectal cancer. Although some potential biochemical targets have been identified, its precise mechanism of action remains unclear. We found that N6-isopentenyladenosine affects colorectal cancer proliferation in in vitro models carrying different mutational status of FBXW7 and TP53 genes, and in HCT116 xenografts in SCID mice, by increasing the expression of the well-established tumor suppressor FBXW7, a component of the SCF-E3 ubiquitin ligase complex that promotes degradation of various oncoproteins and transcription factors, such as c-Myc, SREBP and Mcl1. Corroborating our previous studies, we identified for the first time the FBXW7/SREBP/FDPS axis as a target of the compound. Pull down of ubiquitinated proteins, immunoprecipitation and luciferase assays, reveal that through the increase of FBXW7/c-Myc binding, N6-isopentenyladenosine induces the ubiquitination of c-Myc, inhibiting its transcriptional activity. Moreover, in FBXW7- and TP53-wild type cells, N6-isopentenyladenosine strongly synergizes with 5-Fluorouracil to inhibit colon cancer growth in vitro. Our results provide novel insights into the molecular mechanism of N6-isopentenyladenosine, revealing its multi-targeting antitumor action, in vitro and in vivo. Restoring of FBXW7 tumor-suppressor represents a valid therapeutic tool, enabling N6-isopentenyladenosine as optimizable compound for patient-personalized therapies in colorectal cancer. View Full-Text
Keywords: N6-isopentenyladenosine; colon cancer; FBXW7; mevalonate pathway; 5-fluorouracil; chemoresistance N6-isopentenyladenosine; colon cancer; FBXW7; mevalonate pathway; 5-fluorouracil; chemoresistance
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Fiore, D.; Piscopo, C.; Proto, M.C.; Vasaturo, M.; Dal Piaz, F.; Fusco, B.M.; Pagano, C.; Laezza, C.; Bifulco, M.; Gazzerro, P. N6-Isopentenyladenosine Inhibits Colorectal Cancer and Improves Sensitivity to 5-Fluorouracil Targeting FBXW7 Tumor Suppressor. Cancers 2019, 11, 1456.

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