Research paperInhibition of SUMO-specific protease 1 induces apoptosis of astroglioma cells by regulating NF-κB/Akt pathways
Introduction
SUMOylation is an important post-translational modification which is characterized by SUMO (small ubiquitin-related modifier) proteins covalently binding to intracellular target proteins. SUMO proteins are conjugated to > 200 proteins which display an important effect on protein stability, signal transduction, nucleoplasm transport, transcription regulation, DNA repair, and the regulation and control of cell cycle etc. (Hay, 2005, González-Santamaría et al., 2012). SUMOylation is a dynamic process which can be reversed by a family of SUMO-specific protease (SENP).
Recently, SENP1, a member of SENPs family, was shown to have a pro-oncogenic role in many types of cancer. SENP1 was observed to be overexpressed in lung cancer tissues, and the modulation of SENP1 expression was demonstrated to significantly affect the proliferation of lung cancer cells (Wang et al., 2013). SENP1 regulates cell migration and invasion in neuroblastoma and suppress SENP1 expression as promising candidates for novel treatment strategies of neuroblastoma (Xiang-Ming et al., 2015). SENP1 was also upregulated in pancreatic ductal adenocarcinoma (PDAC) tissues compared with adjacent normal tissues and regulates pancreatic cancer cell proliferation and invasion by targeting MMP-9 (Ma et al., 2014). Inhibition of SENP1 induces apoptosis and growth arrest of multiple myeloma cells through modulation of NF-κB signaling (Xu et al., 2015). In BV2 microglial cells, SENP1 inhibits the IH (Intermittent hypoxia)-induced apoptosis and nitric oxide production (Liu et al., 2015). SENP1 also positively regulated the expression of HIF-1α by deSUMOylation and weakened the sensitivity of hypoxic ovarian cancer cells to cisplatin (Ao et al., 2015). Although the up-regulation of SENP1 was observed in many types of human tumors, the concrete mechanism of SENP1 how regulates astrocytoma development is still unclear. Brain astrocytoma is the most frequent one among the various neurogliomas, the glioblastoma multiforme (GBM) out of which is the most malignant brain glioma subtype. Although there have been treatment methods at present, the prognosis is very poor and the life quality of patients was seriously influenced (Liu et al., 2007). In the process of genesis, development and malignant transformation, the expression of different signaling molecules all can accelerate or delay the progress of patients' condition. NF-κB pathway is considered as one of the treatment targets and in the activated state in GBM, blocking of which facilitated senescence of the differentiated cells (Nogueira et al., 2011). Also, the molecular mechanism underlying constitutive activation of AKT signaling plays essential roles in astrocytoma progression (Cai et al., 2015). To further elucidate the molecular mechanisms by which SENP1 regulates the growth and progression of astrocytoma, we detected the expression of SENP1 in different grade of astrocytoma and whether SENP1 can regulate U87MG and U251 cell apoptosis via NF-κB/Akt pathways.
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Patients and tissue specimens
All the tissue samples were collected from the operative inpatients in the Department of Neurosurgery, the Second Hospital of Hebei Medical University, which was approved by Local and Medical Ethics Committee (Second Hospital of Hebei Medical Research Ethics Committee, Approval No. 2012003). We confirmed that the written informed consent was obtained from the next of kin in this study and the data of samples were analyzed anonymously. Our clinical investigation has been conducted according to
Analysis of SENP1 expression in normal brain and astrocytoma tissues
The expression of SENP1 was detected in 34 tissue samples from control people and patients with astrocytoma by RT-qPCR. The results demonstrated that the expression of SENP1 was significantly increased in the lower (II) and higher (III, IV) grades of astrocytomas in comparison with that in the normal brain tissues (p < 0.01) (Fig. 1A), which was consistent with the RT-PCR result (Fig. 1B). The results suggested that SENP1 had a positive correlation with the tumor malignant degree and might be
Discussion
It has been reported that over 200 intracellular target proteins can be SUMO-modified, including a great number of tumor genesis-related substrate proteins, such as AP-2, AR, c-Jun, c/EBP, c-Myb, CREB, Erm, Ets-1, GATA-2, HDACs, HSF1, IκBα, IRF-1, Pdx1, PTEN, p53, Sp3, STAT1, and TEL etc. (González-Santamaría et al., 2012, Bettermann et al., 2012), which display an important regulation effect on the stability of intracellular homeostasis. As an unique crucial deSUMOylation–specific proteinase,
Acknowledgments
This research was supported by Grants from Beijing Natured Scientific Foundation (No. 7164285) and the Major State Basic Research Development Program of China (973 Program) (No. 2011CB503803).
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