Interestingly, IPA showed also immune-modulating properties activating NK cells-mediated recognition of glioma cells, achieved by the upregulation of ULBP2, NKG2D ligand, in TP53 wild type cells or MICA/B in p53 mutant gliomas. This effect seems to comply with the inhibition of Rab7 prenylation, as expected of IPA ability to inhibit FDPS. It was previously reported that IPA exerts antiangiogenic effect, through activation of AMP-Kinase (AMPK) that allows mTOR inhibition, autophagosome accumulation and late-stage autophagy inhibition. The modified nucleoside’s chemical structure allows IPA to potentially influence multiple pathways, explaining its pleiotropic action. Although it has been largely accepted that IPA inhibits farnesyl diphosphate synthase (FDPS) enzyme, the exact molecular mechanism underlying the antitumor efficacy is still unknown. N6-isopentenyladenosine (IPA) is a member of cytokinin family, found to exert antitumor activity on a wide range of human epithelial cancer cells, including colorectal cancer (CRC). Restoring of FBXW7 tumor-suppressor represents a valid therapeutic tool, enabling N6-isopentenyladenosine as optimizable compound for patient-personalized therapies in colorectal cancer. Our results provide novel insights into the molecular mechanism of N6-isopentenyladenosine, revealing its multi-targeting antitumor action, in vitro and in vivo. Moreover, in FBXW7- and TP53-wild type cells, N6-isopentenyladenosine strongly synergizes with 5-Fluorouracil to inhibit colon cancer growth in vitro. 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. Corroborating our previous studies, we identified for the first time the FBXW7/SREBP/FDPS axis as a target of the compound. 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. Although some potential biochemical targets have been identified, its precise mechanism of action remains unclear.
N6-isopentenyladenosine has been shown to exert potent in vitro antitumor activity on different human cancers, including colorectal cancer.
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