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• W2891673151 abstract "Nuclear pores are nanomachines acting as gatekeepers of molecular transport across nuclear membranes. In a recent issue of Cell, Rodriguez-Bravo et al., 2018Rodriguez-Bravo V. Pippa R. Song W.M. Carceles-Cordon M. Dominguez-Andres A. Fujiwara N. Woo J. Koh A.P. Ertel A. Lokareddy R.K. et al.Nuclear pores promote lethal prostate cancer by increasing POM121-driven E2F1, MYC, and AR nuclear import.Cell. 2018; 174: 1200-1215.e20Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar demonstrates that nuclear pores promote aggressive prostate cancer by snowballing POM121-importin β-driven nuclear import. Treatment with Importazole, an importin β inhibitor, impeded tumor aggressiveness, presenting a potential therapeutic strategy. Nuclear pores are nanomachines acting as gatekeepers of molecular transport across nuclear membranes. In a recent issue of Cell, Rodriguez-Bravo et al., 2018Rodriguez-Bravo V. Pippa R. Song W.M. Carceles-Cordon M. Dominguez-Andres A. Fujiwara N. Woo J. Koh A.P. Ertel A. Lokareddy R.K. et al.Nuclear pores promote lethal prostate cancer by increasing POM121-driven E2F1, MYC, and AR nuclear import.Cell. 2018; 174: 1200-1215.e20Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar demonstrates that nuclear pores promote aggressive prostate cancer by snowballing POM121-importin β-driven nuclear import. Treatment with Importazole, an importin β inhibitor, impeded tumor aggressiveness, presenting a potential therapeutic strategy. Maintenance of normal cellular functions relies on the well-orchestrated cellular signaling that requires perfect communication between cytoplasm and nucleus. Nuclear pore complexes (NPCs) are the only turnstile embedded in the nuclear envelope (NE), acting as a nanoscale communicator between the cytosol and the nucleus (Funasaka and Wong, 2011Funasaka T. Wong R.W. The role of nuclear pore complex in tumor microenvironment and metastasis.Cancer Metastasis Rev. 2011; 30: 239-251Crossref PubMed Scopus (30) Google Scholar, Sakuma and D’Angelo, 2017Sakuma S. D’Angelo M.A. The roles of the nuclear pore complex in cellular dysfunction, aging and disease.Semin. Cell Dev. Biol. 2017; 68: 72-84Crossref PubMed Scopus (66) Google Scholar). NPC is a gigantic protein complex formed by more than 30 proteins known as nucleoporins or Nups. The Nups tracked by their predicted molecular weight are segmental in that a limited number of structural motifs (coiled-coils, α-solenoids, β-propellers) are used repetitively to build the symmetrical NPC structure. NPCs allow molecules with molecular weights less than 40 kDa to pass through to the nucleus via passive diffusion. In contrast, nucleocytoplasmic transport of large proteins is selective and much more complex. Cargo proteins possess either nuclear localization signal (NLS) or nuclear export signal (NES) motifs that are required for nucleocytoplasmic transport. These motifs are recognized by nuclear transport factors, collectively termed importins, exportins, transportins, or karyopherins (also referred to as kaps), which ferry the cargo. A cargo protein with NLS binds with a receptor protein (importin β) and an adaptor protein (importin α) to form a complex before nuclear translocation. Similarly, a cargo protein with NES binds with an exportin to form a complex before it is exported out to cytoplasm (Hoelz and Blobel, 2004Hoelz A. Blobel G. Cell biology: popping out of the nucleus.Nature. 2004; 432: 815-816Crossref PubMed Scopus (40) Google Scholar, Wong, 2015Wong R.W. Nuclear pore complex: from structural view to chemical tools.Chem. Biol. 2015; 22: 1285-1287Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar). The assembly and disassembly of cargo-nuclear transporter complexes is controlled by Ran, a protein that can have two conformational distinct states determined by whether it is bound to nucleotide guanine triphosphate (GTP) or to guanine diphosphate (GDP) (Nakano et al., 2011Nakano H. Wang W. Hashizume C. Funasaka T. Sato H. Wong R.W. Unexpected role of nucleoporins in coordination of cell cycle progression.Cell Cycle. 2011; 10: 425-433Crossref PubMed Scopus (38) Google Scholar). The selective nature of nucleocytoplasmic transport implies the importance of subcellular localization of proteins in maintaining the homeostasis of cellular signaling within a cell. Dysregulation of cellular signaling is common in cancer cells. Aberrant nucleocytoplasmic transport causes mislocalization of proteins, particularly transcription factors and tumor suppression proteins, and hence leads to disturbance of the homeostasis of cellular signaling in cells, which is important for carcinogenesis. Mislocalization of proteins in subcellular compartments can directly diminish their primary functions in cells even when they exist in wild-type form. For example, accumulation of wild-type p53 proteins in cytoplasm has been found in solid tumors. These cytoplasmic-localized p53 proteins still possess tumor suppressive function but the function cannot be carried out as the proteins are unable to translocate to nucleus (Hill et al., 2014Hill R. Cautain B. de Pedro N. Link W. Targeting nucleocytoplasmic transport in cancer therapy.Oncotarget. 2014; 5: 11-28Crossref PubMed Scopus (75) Google Scholar). Likewise, nuclear translocation of oncoproteins into nucleus induces proliferation, survival, invasion, and migration. Nucleoporin-associated mislocalizations of proteins are not only essential for tumorigenesis but also necessary for cancer cells to evolve to become much more aggressive and lethal phenotypes (Figure 1A). Interestingly, mutation of nucleoporins resulting to carcinogenesis is sporadic. Nucleoporins are commonly found to be fused with other proteins to promote cancer development. For example, NUP98 fusion proteins are important in leukemogenesis and the tyrosine kinase fusion protein, TPR-Met, produces constitutively active met kinase (Köhler and Hurt, 2010Köhler A. Hurt E. Gene regulation by nucleoporins and links to cancer.Mol. Cell. 2010; 38: 6-15Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar). However, the direct role of NPCs in carcinogenesis still remains elusive. New findings from the Rodriguez-Bravo and Domingo-Domenech Laboratories now expand on NPCs carcinogenesis by revealing a novel role for the transmembrane NPC component POM121. Rodriguez-Bravo et al., 2018Rodriguez-Bravo V. Pippa R. Song W.M. Carceles-Cordon M. Dominguez-Andres A. Fujiwara N. Woo J. Koh A.P. Ertel A. Lokareddy R.K. et al.Nuclear pores promote lethal prostate cancer by increasing POM121-driven E2F1, MYC, and AR nuclear import.Cell. 2018; 174: 1200-1215.e20Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar present a comprehensive study on direct contribution of NPCs in the development of aggressive prostate cancer (Figure 1B). The team has observed distinct expression patterns in various types of nucleoporins between primary prostate cancer and metastatic prostate cancer. POM121, NUP188, NUP210, NUP85, NUP62, NUP214, and TPR were significantly high in metastatic prostate cancer compared with primary prostate cancer. Among these Nups, POM121 upregulation was the greatest. Furthermore, transmission electron microscopy (TEM) imaging revealed morphological differences in nuclear envelope between primary and aggressive prostate cancers. Exogenous POM121 promoted tumorigenesis, proliferation, and therapeutic resistance in prostate cancer cell lines. Moreover, in vivo study revealed that depletion of POM121 delayed tumor formation, suppressed tumor proliferation, and improved efficacy of chemotherapy. The oncogenic role of POM121 relies on its nucleocytoplasmic transport function, as depletion of POM121 did not affect the integrity of nuclear pore complex and localization of POM121 in NPC is compulsory for the development of aggressive phenotype of prostate cancer. POM121 has a single N-terminal transmembrane domain trailed by an extra membranous region comprising two putative bipartite NLSs that interact with importin α and importin β. Interaction between POM121 and importin β was crucial for enhancing aggressiveness of prostate cancer through nuclear translocation of importin-dependent key oncogenic transcription factors MYC and E2F1 and prostate cancer-specific transcription factors AR and GATA2. Intriguingly, GATA2 regulated the expression of POM121 via GATA2-binding elements (GBE1-3) located in the POM121 promoter region. The active communication between GATA2 and POM121 was indispensable for nuclear import of GATA2 and subsequently increased aggressiveness of prostate cancer. These results suggest that disruption of nucleocytoplasmic transport mediated by POM121 and importin β is a practical therapeutic strategy to treat prostate cancer. In vitro study unraveled that the importin β inhibitor, Importazole, exerted its anti-tumorigenic effects and proved to be a potential candidate for combination therapy with chemotherapy and radiotherapy. Furthermore, Importazole impeded the development of an aggressive phenotype of prostate cancer by blocking nuclear import of E2F1, MYC, and GATA2. A xenograft model demonstrated that Importazole reduced tumor load, enhanced chemotherapeutic effects, and improved survival (Figure 1C). In summary, POM121-importin β interaction is a potential druggable candidate for prostate cancer. The report by Rodriguez-Bravo et al., 2018Rodriguez-Bravo V. Pippa R. Song W.M. Carceles-Cordon M. Dominguez-Andres A. Fujiwara N. Woo J. Koh A.P. Ertel A. Lokareddy R.K. et al.Nuclear pores promote lethal prostate cancer by increasing POM121-driven E2F1, MYC, and AR nuclear import.Cell. 2018; 174: 1200-1215.e20Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar emphasizes the importance of nucleocytoplasmic transport in carcinogenesis and cancer progression. Potential therapeutic chemical biology approaches that focus on nuclear transport machinery are crucial to improve current standard treatments for cancers. There are several strategies that are useful to suppress carcinogenesis and reactivate tumor suppressor function by maintaining the proper localization of proteins in cells. This can be achieved by using drugs to modulate nuclear import and nuclear export in cancer cells. Nuclear import of oncoproteins can be blocked by drugs through several mechanisms other than interfering with the interaction between oncoproteins and Nups, such as disruption of the interaction between receptor and RanGTP and blockade of cargo/receptor complex formation via competitive inhibition. Similarly, nuclear export of tumor suppressor proteins can be prevented using nuclear export inhibitors. Prostate cancer is the most common non-skin cancer around the world. In the United States, every 1 in 9 men are diagnosed with prostate cancer in their lifetime. Most men with primary prostate cancer do not have any symptoms or signs. But every cloud has a silver lining, and this axis could be an ideal therapeutic marker for prostate cancer patients to receive effective treatments. Nuclear Pores Promote Lethal Prostate Cancer by Increasing POM121-Driven E2F1, MYC, and AR Nuclear ImportRodriguez-Bravo et al.CellAugust 9, 2018In BriefPOM121- and importin β-mediated nuclear import of a subset of oncogenic transcription factors promotes prostate cancer aggressiveness and reveals a pharmacologically targetable dependency. Full-Text PDF Open Archive" @default.
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• W2891673151 title "Targeting Nucleoporin POM121-Importin β Axis in Prostate Cancer" @default.
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