Abstract
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.
Highlights
N6-isopentenyladenosine (IPA) is a member of cytokinin family [1], found to exert antitumor activity on a wide range of human epithelial cancer cells [2], including colorectal cancer (CRC) [3,4].Cancers 2019, 11, 1456; doi:10.3390/cancers11101456 www.mdpi.com/journal/cancers it has been largely accepted that IPA inhibits farnesyl diphosphate synthase (FDPS)enzyme [5,6], the exact molecular mechanism underlying the antitumor efficacy is still unknown.The modified nucleoside’s chemical structure allows IPA to potentially influence multiple pathways, explaining its pleiotropic action
It has been largely accepted that IPA inhibits farnesyl diphosphate synthase (FDPS)
We reported that IPA significantly inhibited DLD1 and HCT116 CRC cells proliferation, in a doseand time-dependent manner, starting from 5 μM after 24 h of treatment (Figure 1A,B)
Summary
N6-isopentenyladenosine (IPA) is a member of cytokinin family [1], found to exert antitumor activity on a wide range of human epithelial cancer cells [2], including colorectal cancer (CRC) [3,4].Cancers 2019, 11, 1456; doi:10.3390/cancers11101456 www.mdpi.com/journal/cancers it has been largely accepted that IPA inhibits farnesyl diphosphate synthase (FDPS)enzyme [5,6], the exact molecular mechanism underlying the antitumor efficacy is still unknown.The modified nucleoside’s chemical structure allows IPA to potentially influence multiple pathways, explaining its pleiotropic action. N6-isopentenyladenosine (IPA) is a member of cytokinin family [1], found to exert antitumor activity on a wide range of human epithelial cancer cells [2], including colorectal cancer (CRC) [3,4]. It has been largely accepted that IPA inhibits farnesyl diphosphate synthase (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. This effect seems to comply with the inhibition of. As expected of IPA ability to inhibit FDPS [7,8]. Among the identified molecular mechanisms, in glioblastoma multiforme (GBM), IPA induces c-Cbl-mediated EGFR ubiquitination, inhibiting its downstream signaling [10]
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