ReviewNuclear transport as a target for cell growth
Section snippets
Nuclear transport of proteins
One of the hallmarks of eukaryotic cells is the containment of DNA in the cell nucleus, where transcription and replication are separated from protein synthesis in the cytoplasm. Transport of molecules between the cytoplasm and nucleus occurs across the nuclear envelope through the nuclear pore complex (NPC), a large protein structure of ∼125 megadaltons (MDa) that enables the passage of a variety of complexes, up to 120 kDa, the size of the large ribosomal subunit [1]. In principle, molecules
Nuclear export inhibitor leptomycin B as a cancer therapeutic
Isolated from a Streptomyces strain, leptomycin B (LMB) has, until recently, been the only known small-molecule inhibitor of nuclear transport. Leptomycin B is an unsaturated branched-chain fatty acid (Fig. 2) and has been shown to have antifungal, antibacterial and anti-tumor activity 6., 7., 8.. Furthermore, LMB causes cell-cycle arrest at stages G1 and G2 of the cell cycle in yeast and mammalian cells [9]. Leptomycin B was first implicated as an inhibitor of nuclear export in a screen for
Targeting nuclear localization of key transcription factors in disease
Several well-characterized transcription factors have been implicated in tumorigenesis. As transcription occurs in the cell nucleus, the activity of these factors can be regulated by their subcellular localization 23., 24.. Thus, identifying small molecules that affect the localization of transcription factors can be an effective target for the control of unwanted cell growth.
Moving proteins with peptide aptamers
In contrast to inhibiting the endogenous signaling pathways of a cell to re-localize effectors of cell death or cell growth, peptide aptamers enable the active targeting of effectors to the nucleus or cytoplasm. Analogous to monoclonal antibodies, peptide aptamers are small proteins that contain a structurally constrained variable region of ∼20 amino acids, expressed as part of an inert scaffold such as thioredoxin or green fluorescent protein [70]. Peptide aptamers that have been created
Future implications
Using small molecules or peptide aptamers to alter the cellular localization of a protein can reveal much about its cell biology. In addition, the spatial localization of a target offers another dimension or variable that researchers could exploit to control cancer cell growth. This review has described several methods for targeting nuclear transport, and these methods can range widely, from inhibiting the general protein transport machinery, to using small-molecule protein or lipid-kinase
Acknowledgements
We would like to thank Charles Cho, Paul Ko Ferrigno and Jason Casolari for their helpful comments, and Eric Smith for providing the artwork.
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A phase 1b trial of selinexor, a first-in-class selective inhibitor of nuclear export (SINE), in combination with doxorubicin in patients with advanced soft tissue sarcomas (STS)
2021, European Journal of CancerCitation Excerpt :Overexpression or dysfunction of XPO1 in a variety of solid and haematological tumours has been associated with poorer outcomes [12]. XPO1 blockade causes the transient nuclear retention of TSPs and other growth modulators, re-establishing their tumour suppressing and growth regulating effects on cancer cells and potentially reversing mechanisms leading to chemotherapy resistance [13,14]. In normal cells, XPO1 inhibition transiently arrests the cell cycle without cytotoxicity followed by recovery after the inhibitor is removed [13,15].
A closer look on various synthetic routes to Callystatin A: a cytotoxic marine sponge polyketide
2017, Tetrahedron AsymmetryCitation Excerpt :It was first isolated in 1997 from the marine sponge Callyspongia truncata which was collected from the Goto Islands in the Nagasaki Prefecture of Japan by Kobayashi et al.5 It displays promising antitumor activity with an IC50 value of 10 pg/mL against human epidermoid carcinoma KB tumor cells and 20 pg/mL against mouse lymphocytic leukemia L1210 cells.1,5 Structure–activity relationship studies have shown that the δ-lactone is the main pharmacophore, even though no increment in bioactivity through analogue synthesis has been evinced.6 Partial and total synthesis together with NMR spectroscopic data established the relative and absolute stereochemistry of (−)-Callystatin A.7
KPNA2 predicts long term survival in patients with anaplastic oligoastrocytomas
2014, Journal of Clinical NeuroscienceCitation Excerpt :KPNA2 overexpression in breast tumor cells has been found to increase proliferation and cell migration in a tumor model, while RNA interference-mediated KPNA2 silencing causes a complete inhibition of proliferation and migration of the breast cancer cells [35]. On the other hand, CRM1 overexpression in various cancers is related to increased nuclear export of tumor suppressor proteins, cell cycle inhibitors or chemotherapeutic target proteins [36–39]. Of note, CRM1 is the sole exporter of key tumor suppressors, such as the p53 protein [40,41].
The importance of oncogenic transcription factors for oral cancer pathogenesis and treatment
2013, Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology