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

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.

Modified Adenosines Sensitize Glioblastoma Cells to Temozolomide by Affecting DNA Methyltransferases

“…However, the multitude of their effects described in numerous studies ( Laezza et al, 2009 ; Ottria et al, 2010 ; Ciaglia et al, 2014 ; Ciaglia et al, 2017a ; Ciaglia et al, 2017b ; Dassano et al, 2014 ; Pisanti et al, 2014 ; Ciaglia et al, 2018 ; Ranieri et al, 2018 ), and the chemical nature of these molecules, suggests that a precise mechanism explaining their pleiotropic effects in different tumor-related mechanisms, ranging from the tumor microenvironment to immunomodulation, has not yet been fully identified. Recently, we reported that IPA inhibits colorectal cancer (CRC) proliferation in vitro and in vivo by increasing the expression of the tumor suppressor FBXW7 and, in turn, regulating the FBXW7/SREBP/FDPS axis, corroborating with previous studies ( Fiore et al, 2019 ). FBXW7 is a component of the SCF-E3 ubiquitin ligase complex responsible for the degradation of various oncoproteins and transcription factors, such as p100/NFκB, HIF-1α, c-Myc, SREBP, and Mcl1 ( Sailo et al, 2019 ).…”

“…Moreover, in vitro FBXW7 overexpression significantly suppressed proliferation, invasion, and migration and, most importantly, was found to increase temozolomide (TMZ) toxicity in a resistant clone ( Lin et al, 2018 ). We previously found that, in FBXW7 - and TP53 -wild-type CRC cells, IPA-mediated restoration of FBXW7 tumor suppressor translates into synergism with 5-fluorouracil ( Fiore et al, 2019 ).…”

S-Adenosyl-l-Methionine Overcomes uL3-Mediated Drug Resistance in p53 Deleted Colon Cancer Cells

“…Although many mechanisms of tumor chemoresistance have been discovered and elucidated, it remains the leading cause of chemotherapy failure, especially in relapsed or metastatic tumors. Re-sensitizing cancer cells to the drugs by using novel effective strategies is a promising approach to overcome the chemoresistance and improve clinical treatment [ 38 , 39 ]. Recently, we evaluated uL3 clinical significance in colon cancer and demonstrated that uL3 expression in colon tumor tissues is downregulated; in particular, the decrease in uL3 mRNA levels associated with malignance progression and tumor grade and were inversely proportional to the ratio Bcl-2/Bax [ 15 ].…”

The role of ubiquitination and deubiquitination in cancer metabolism

“…Mutation or deletion of these E3 ligase genes induces carcinogenesis by attenuating c-Myc degradation. Anticancer drugs, including lanatoside C, diminish cancer cell growth by upregulating ubiquitination and degradation of c-Myc in cancer [161][162][163]. Ubiquitination of c-Myc can also be regulated by interaction with other molecules.…”