Our recent studies found that isorhapontigenin (ISO) showed a significant inhibitory effect on human bladder cancer cell growth, accompanied with cell cycle G0/G1 arrest as well as down-regulation of Cyclin D1 expression at transcriptional level via inhibition of Sp1 transactivation in bladder cancer cells. In current studies, the potential ISO inhibition of bladder tumor formation has been explored in xenograft nude mouse model, and the molecular mechanisms underlying ISO inhibition of Sp1 expression and anti-cancer activities has been elucidated both in vitro and in vivo. Moreover, the studies demonstrated that ISO treatment induced the expression of miR-137, which in turn suppressed Sp1 protein translation by direct targeting Sp1 mRNA 3′UTR. Similar to ISO treatment, ectopic expression of miR-137 alone led to G0/G1 cell growth arrest and inhibition of anchorage-independent growth in human bladder cancer cells, which could be completely reversed by over-expression of GFP-Sp1. The inhibition of miR-137 expression attenuated ISO-induced the inhibition of Sp1/Cyclin D1 expression, and induction of G0/G1 cell growth arrest and suppression of cell anchorage-independent growth. Taken together, our studies have demonstrated that miR-137 induction by ISO targets Sp1 mRNA 3′UTR and inhibits Sp1 protein translation, which consequently results in reduction of Cyclin D1 expression, induction of G0/G1 growth arrest and inhibition of anchorage-independent growth in vitro and in vivo. Our results have provided novel insights into understanding the anti-cancer activity of ISO in the therapy of human bladder cancer.
Background: Nucleolin is a multifunctional protein, but nucleolin-SUMO is unexploited. Results: Nucleolin-SUMO at Lys-294 facilitated binding with mRNA substrate gadd45␣ by maintaining its nuclear localization during cellular response to arsenite exposure. Conclusion: Nucleolin-SUMO promoted arsenite-induced apoptosis by increasing GADD45␣ expression. Significance: We identified a new modification of nucleolin and its contribution to the functional paradigm of nucleolin in mRNA stability regulation.
Emerging evidence from The Cancer Genome Atlas (TCGA) has revealed that nfκb2 gene encoding p100 is genetically deleted or mutated in human cancers, implicating NFκB2 as a potential tumor suppressor. However, the molecular mechanism underlying the anti-tumorigenic action of p100 remains poorly understood. Here, we report that p100 inhibits cancer cell anchorage-independent growth, a hallmark of cellular malignancy, by stabilizing the tumor suppressor PTEN mRNA via a mechanism that is independent of p100’s inhibitory role in NFκB activation. We further demonstrate that the regulatory effect of p100 on PTEN expression is mediated by its downregulation of miR-494 as a result of the inactivation of ERK2, in turn leading to inhibition of c-Jun/AP-1-dependent transcriptional activity. Furthermore, we identify that p100 specifically interacts with non-phosphorylated ERK2 and prevents ERK2 phosphorylation and nuclear translocation. Moreover, the death domain at C-terminal of p100 is identified as being crucial and sufficient for its interaction with ERK2. Taken together, our findings provide novel mechanistic insights into the understanding of the tumor suppressive role for NFκB2 p100.
Background: Messenger RNA of hif-1␣ could be regulated by post-transcriptional mechanisms. Results: Depletion of either JNK2 or nucleolin affected hif-1␣ mRNA stability. Conclusion: JNK2 regulated nucleolin expression and might in turn stabilize hif-1␣ mRNA. Significance: We provided more evidence for the oncogenic roles of JNK2 and nucleolin in regulating the cancer microenvironments by controlling HIF-1␣ expression.
Cheliensisin A (Chel A), a novel styryl-lactone isolated from Goniothalamus cheliensis Hu, has been shown to induce of apoptosis in human promyelocytic leukemia HL-60 cells with Bcl-2 downregulation. Yet the potential chemopreventive effect of Chel A has not been explored. Here we demonstrated that Chel A treatment with various concentrations (0.5, 1.0, 2.0, and 4.0 μM) for 3 weeks could dramatically inhibit EGF-induced cell transformation in Cl41 cells (IC50 approximately 2.0 μM). Also, co-incubation of Cl41 cells with Chel A (2.0 and 4.0 μM) for 48 hours could induce cell apoptosis in a caspase-3-dependent manner. Mechanically, Chel A treatment could result in increased p53 phosphorylation at Ser15 and elevated p53 total protein expression. Moreover, we found that p53 induction by Chel A was regulated at the protein degradation level, but not at either the transcription or the mRNA level. Further studies showed that p53 stabilization by Chel A was mediated via induction of phosphorylation and activation of Chk1 protein at Ser345. This notion was substantiated by the results that transfection of dominant negative mutant of Chk1 (GFP-Chk1 D130A) significantly attenuated the p53 protein expression, cell apoptosis, and inhibition of cell transformation by Chel A. Finally, increased hydrogen peroxide was found to mediate Chk1 phosphorylation at Ser345, p53 protein induction, cell apoptotic induction, and transformation inhibition following Chel A treatment. Taken together, our studies identify Chel A as a chemopreventive agent with the understanding of the molecular mechanisms involved.
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