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  • Nucleophosmin NPM which also plays a role on the nuclear

    2020-08-03

    Nucleophosmin (NPM1), which also plays a role on the nuclear export of ribosomal proteins and subunits (Maggi et al., 2008), is also a relevant MYC target, presumably through an interaction with CRM1. Conversely, it has been recently reported that specific SINE compounds reduce the levels of MYC in MM tcs products (Tai et al., 2014) and MCL (Tabe et al., 2013). Because the nuclear export of Myc mRNA is mediated by CRM1(Culjkovic et al., 2006), it is certainly possible that CRM1 and MYC maintain their interrelationships in ribosomal biogenesis. Tabe and Kojima, et al. (Tabe et al., 2013, Yoshimura et al., 2014) have very recently analyzed the pro-survival pathways involved in CRM1-dependent nuclear export in MCL cells, using the isobaric tags for relative and absolute quantification (iTRAQ) with two-dimensional-liquid chromatography-tandem mass spectrometry. iTRAQ proteomics of two MCL cell lines revealed that 75 proteins were consistently altered after KPT-185 treatment. Notably, 81% (i.e., 50/62) of the downregulated proteins were ribosomal proteins consisting of both 60S and 40S subunits. A marked suppression of the eukaryotic translation initiation factor 4A1 and eukaryotic elongation factor 2 in these cells suggested that KPT-185 inhibited the CRM1-dependent nuclear export of ribosomal subunits, which led to a defect of ribosomal biogenesis. Recently, the coordination between the net translational activity of ribosomal biogenesis and the transcriptional regulation of heat shock factor 1 has been reported (Santagata et al., 2013). In fact, KPT-185 induced a decrease of heat shock factor 1 targets (e.g., HSP70, FASN, phosphor-HSP90, and EEF1A1), and increased the levels of phosphor-hnRNP D presumably due to the inhibition of translational activity resulting from a decrease in ribosomal protein or RNA. These results indicate that CRM1 may also affect the transcriptional processes that are critical for cellular metabolism and survival (Kohler and Hurt, 2007, Tabe et al., 2013).
    Inhibitors of the CRM1 protein Overexpression of CRM1 and its correlation with negative clinical outcomes in various malignancies has recently been reported, and, given this association, the protein is predicted to be a promising therapeutic target in oncology (Noske et al., 2008, Huang et al., 2009, Shen et al., 2009, Yao et al., 2009, Ranganathan et al., 2012, Yoshimura et al., 2014). Indeed, it has been shown that blocking CRM1-mediated nuclear export of any, or all, of these proteins by siRNA or SINE compounds activates apoptotic pathways and increases tumor cell sensitivity to chemotherapeutic drugs such as doxorubicin (Turner et al., 2009), etoposide (Turner et al., 2009), cisplatin (Takenaka et al., 2004), and imatinib mesylate (Vigneri and Wang, 2001, Aloisi et al., 2006). Based on the structure-function relationship seen in the natural product CRM1 inhibitors leptomycin B, ratjadone (Meissner et al., 2004), anguinomycin (Bonazzi et al., 2007), and goniothalamin (Wach et al., 2010), recently-developed small molecule inhibitors of CRM1, such as N-azolylacrylates (Daelemans et al., 2002, Van Neck et al., 2008), KOS-2464 (Mutka et al., 2009), and CBS9106 (Sakakibara et al., 2011) have clearly demonstrated the requirement of CRM1 nuclear export activity for the growth and survival of cancer cells. The following sections will discuss these agents in detail.