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  • The molecular mechanism by which CRM regulates IEC


    The molecular mechanism by which CRM1 regulates IEC apoptosis in CD remains to be explored. As an inhibitor of cyclin E-Cdk2, p27kip1 plays a pivotal role in controlling cell proliferation, S phase entry, and G1 phase exit during development and tumorigenesis [38]. As previously reported, p27kip1 is a tumor suppressor gene, the loss of which, in parallel with mutations in several oncogenes and tumor suppressor genes, facilitates tumor growth [39]. Several laboratories have reported that the cytoplasmic localization of p27kip1 promotes its oncogenic activity. Akt–, ERK2–, CDK5- or hKIS-mediated p27kip1 phosphorylation at ser10 promoted CRM1-mediated nuclear export [40]. Furthermore, p27kip1 has been reported to play a crucial role in TBI via CRM1-mediated p27kip1 export from the nucleus to the cytoplasm during the G0–G1 phase [27], [41] via the SKP2-independent pathway for degradation [42] and to then promote DNA damaged neurons to re-enter the cell cycle, leading to neuronal apoptosis via caspase-3 activation. Interactions between CRM1 and p27kip1 in the cortex after injury have also been reported [20]. P27kip1 has been shown to be dysregulated in IBD-associated neoplasia, and loss of p27kip1 protein expression has been associated with aggressive behavior in IBD-associated neoplasia [21]. Experimental glomerulonephritis induced in p27kip1 gene knockout mice led to increased epithelial cell injury, suggesting a protective role of p27kip1 in inflammatory conditions [43]. In this study, we discovered that CRM1 was increased in the intestinal tissues of patients with active CD in whom ser10-phosphorylated p27 was also elevated, whereas the expression of p27kip1 was decreased. In vitro experiments revealed that increased expression of CRM1 was consistent with elevated ser10-phosphorylated p27 at 48h post-TNF-α administration in HT-29 cells. The physical interaction between CRM1 and p27kip1 in TNF-α-treated HT-29 a66 synthesis was further confirmed through co-immunoprecipitation assays. The nuclear and cytoplasmic extraction protocol demonstrated that TNF-α enhanced the cytoplasmic accumulation of CRM1 and p27kip1, indicating that translocated CRM1 and p27kip1 to the cytoplasm may be involved in elevated cell apoptosis. Furthermore, CRM1 knockdown by siRNA attenuated TNF-α-induced p27 phosphorylation at ser10 and resulted in up-regulation of p27kip1 in HT-29 cells. These results suggested that CRM1 regulation of IEC apoptosis might be partly mediated by the suppression of p27kip1 activation.
    Disclosure of interest
    Acknowledgements This work was supported by National Natural Science Foundation of China (81470806); The Natural Science Foundation of Jiangsu Province Grant (BK20141496).
    Introduction The medicinal effects of Lai Fu Zi (Raphanus sativus) have been documented since the Song dynasty for over one thousand years in traditional Chinese medicine to treat symptoms such as coughing and food stagnation [1]. The major active component of Lai Fu Zi is a naturally-derived isothiocyanate compound named as sulforaphene (LFS-01, Fig. 1a), which has recently raised considerable research interests worldwide for its excellent therapeutic activities yet with minimal side effects. However, the exact mechanism of action for LFS-01 in malignant cells is still poorly understood and remains to be clearly defined. Interestingly, we found that LFS-01 can induce apoptosis in numerous lymphoma cell lines while sparing normal lymphocytes isolated from healthy donors. More interestingly, the effects of LFS-01 in lymphoma cells are only partially suppressed by caspase inhibitors, strongly implicating that LFS-01 may also exert its potent antitumor effects through caspase-independent cellular death. Mitophagy refers to the selective degradation of defective mitochondria by autophagy in response to stress conditions [2]. This cargo-specific autophagy involves a few distinct steps to selectively engulf damaged mitochondria into double-membraned vesicles called autophagosomes, in which LC3-II and p62 act as essential structural components [3]. Noteworthy, a very recent study particularly suggests that p62 is crucial for mitophagic clearance and depletion of p62 in cells directly disrupts mitophagy [4]. Furthermore, mammalian target of rapamycin (mTOR) kinase was recently identified as a master regulator of autophagy or mitophagy [5]. Once activated, mTOR can inhibit autophagy or mitophagy followed by reformation of lysosomes [6]. Conversely, AMP-activated protein kinase (AMPK), a key energy sensor, has been recently found to promote mitophagy via negative regulation of mTOR in response to nutrient deprivation or environmental stress [7,8]. Accumulating evidences suggest that mitophagy plays an important role in the regulation of malignant cell survival and metabolism under low-energy or stress conditions. Interestingly, mitophagy could be pro- or anti-tumorigenic depending on tumor stage. For instance, decreased mitophagy may enable dysfunctional mitochondria to persist and thereby generate increased tumor-promoting reactive oxygen species (ROS) or other tumorigenic mitochondrial signals [9]. Consequently, agents that induce mitophagy could exert anti-tumor effects through the clearance of dysfunctional mitochondria. In addition, it has been shown that mitophagy-deficient mice are susceptible to increased tumorigenesis [10]. Such initial findings have raised the possibility that mitophagy could be a novel target for the anti-neoplastic responses of cancer therapeutics.