1. Leptomycin B inhibits the proliferation, migration, and invasion of cultured gastric carcinoma cells
Hepan Zhu, Yi Yang, Li Wang, Xiaobin Xu, Tingting Wang, Haoran Qian Biosci Biotechnol Biochem. 2020 Feb;84(2):290-296. doi: 10.1080/09168451.2019.1673148. Epub 2019 Oct 16.
Chromosome region maintenance 1 (CRM1) plays a critical role in tumorigenesis and progression through modulating nuclear export of several proteins. However, the precise effects of CRM1 inhibitor on gastric carcinoma have not yet been illustrated. Here, we investigated the potential anti-cancer activities of leptomycin B, the most potent CRM1 antagonist, on cultured gastric carcinoma cells. Our findings demonstrate that CRM1 was highly expressed in four gastric carcinoma cell lines. Leptomycin B inhibited the viability of HGC-27 and AGS cells in a dose- and time-dependent pattern. Leptomycin B at the dose of 10 nM or 100 nM suppressed the migration and invasion of HGC-27 and AGS cells. Leptomycin B elevated the expressions of autophagy-related protein LC3-II and autophagy substrate p62. Moreover, leptomycin B enhanced the LC3-positive puncta formation in cells. Our data suggest that leptomycin B may exert an anti-cancer activity possibly through interfering autophagy function in gastric carcinoma cells.
2. A Nuclear Export Signal Is Required for cGAS to Sense Cytosolic DNA
Hong Sun, et al. Cell Rep. 2021 Jan 5;34(1):108586. doi: 10.1016/j.celrep.2020.108586.
The cyclic GMP-AMP (cGAMP) synthase (cGAS) is a key DNA sensor that initiates STING-dependent signaling to produce type I interferons through synthesizing the secondary messenger 2'3'-cGAMP. In this study, we confirm previous studies showing that cGAS is located both in the cytoplasm and in the nucleus. Nuclear accumulation is observed when leptomycin B is used to block the exportin, CRM1 protein. As a result, leptomycin B impairs the production of interferons in response to DNA stimulation. We further identify a functional nuclear export signal (NES) in cGAS, 169LEKLKL174. Mutating this NES leads to the sequestration of cGAS within the nucleus and the loss of interferon response to cytosolic DNA treatment, and it further determines the key amino acid to L172. Collectively, our data demonstrate that the cytosolic DNA-sensing function of cGAS depends on its presence within the cytoplasm, which is warranted by a functional NES.
3. Trichostatin and leptomycin. Inhibition of histone deacetylation and signal-dependent nuclear export
M Yoshida, S Horinouchi Ann N Y Acad Sci. 1999;886:23-36. doi: 10.1111/j.1749-6632.1999.tb09397.x.
Trichostatin A (TSA), an inhibitor of the eukaryotic cell cycle and an inducer of morphological reversion of transformed cells, inhibits histone deacetylase (HDAC) at nanomolar concentrations. Recently, trapoxin, oxamflatin, and FR901228, antitumor agents structurally unrelated to TSA, were found to be potent HDAC inhibitors. These inhibitors activate expression of p21Waf1 and 16INK4A in a p53-independent manner. Changes in the expression of these cell cycle regulators by an increase in histone acetylation may be responsible for cell cycle arrest and antitumor activity by HDAC inhibitors. The target molecule of leptomycin B (LMB), a potent antitumor agent, was genetically and biochemically identified as CRM1, a protein reported as being required for chromosome structure control. We showed that CRM1 was a receptor for the nuclear export signal (NES) and that LMB inhibited nuclear export of proteins. Using LMB, we identified a novel NES in fission yeast transcription factor Pap1, the function of which is abolished by oxidative stress in a manner conserved in eukaryotes.
