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    • In this study we demonstrated that DRR protein level in

    2023-01-28

    In this study, we demonstrated that DRR1 protein level in GBM tissues was significantly higher compared to normal dl 1559 sale tissues. This data suggested that DRR1 might play a role in the tumorigenesis of glioma. To investigate whether DRR1 could accurately predict the outcome in patients with glioma, IHC was performed in 102 archived paraffin-embedded glioma samples. Interestingly, the expression of DRR1 in GBM closely correlated with pathological grade and KPS score (Table 1). Upon analyzing the levels of the proteins encoded by DRR1, we found that the mean levels of DRR1 were significantly higher in grade IV gliomas (GBM) than in grade III gliomas. Moreover, the upregulation of DRR1 protein was significantly associated with a poor outcome of GBM patients, which suggested that the expression of DRR1 is an important and independent source of prognostic information for patients with GBM. In terms of DRR1 mechanisms, we demonstrated, for the first time, that DRR1 plays a critical role in promoting EMT, at least in part, through the activation of AKT. DRR1 has been known as a candidate tumor suppressor gene located on chromosome 3p21.1 [38]. Downregulated DRR1 expression was reported in various types of cancer, such as non-small cell lung, renal cell, and prostate cancers [[39], [40], [41]]. Conversely, upregulation of DRR1 expression was shown to suppress tumor cell proliferation and induce apoptosis [42,43]. However, recent studies showed that DRR1 was also highly expressed in the invasive component of gliomas and may drive tumor invasion by modulating the cytoskeleton [13]. Thus, DRR1 gene may have a dual function in tumor biological behaviors that induces apoptosis in the early stage of tumors and promotes invasion and metastasis in different cancers. EMT is a major molecular event that increases the malignancy in glial tumors [44]. Loss of E-cadherin and acquisition of vimentin are two critical steps in EMT. The Snail family members, Snail and Slug, also play a critical role in EMT during embryonic development and tumor progression [45]. In this study, we found that depletion of DRR1 increased the expression of E-cadherin, while it decreased N-cadherin, Snail, and Slug. These results imply that DRR1 may regulate the EMT of GBM cells. Several signal transduction pathways are known to regulate EMT [46]. Among these pathways, oncogenic activation of the serine-threonine protein kinase AKT (also known as protein kinase B) has emerged as a central feature of EMT [47]. Moreover, mounting evidence indicates that AKT activation plays a significant role in cancer cell invasion through EMT, which is regulated by upregulated higher Snail and Slug expression, thereby leading to the down-regulation of epithelial marker E-cadherin [48]. In this study, we also observed the inhibition of phosphorylation of AKT after DRR1 downregulation in SHG44 and U373 cells. Moreover, the inhibition of AKT activation significantly suppressed the expression of N-cadherin, Snail, and Slug and increased the expression of E-cadherin. The DRR1-mediated promotion of invasion could potentially be blocked by the inhibition of AKT activation. Based on these findings, we speculated that DRR1 promotes EMT, at least in part, through the activation of AKT. The correlation between DRR1 and EMT factors may therefore explain the enhanced invasiveness of GBM cells, which implies that the DRR1 is a promising therapeutic target for GBM. In addition, cancer cells degrade the extracellular matrix layer to invade other organs by inducing matrix metalloproteinases [49]. In our study, we also found that depletion of DRR1 decreased the expression of MMP-7, which is mainly associated with tumor invasion and aggressiveness. Thus, MMP-7 expression may also be involved in the mechanism of DRR1 promoting GBM cell invasion.
    Conclusions
    Conflicts of interest statement
    Introduction Glutamine is a versatile nutrient that contributes to many aspects of metabolism [1,2]. Glutamine serves as an important anaplerotic substrate for tricarboxylic acid (TCA) cycle and plays a unique role in the metabolism of proliferating cells [[1], [2], [3], [4]]. In addition to supporting ATP production, it also provides carbon backbone for the biosynthesis of proteins, lipids and nucleic acids [[5], [6], [7], [8]]. An equally important role played by glutamine is maintaining the redox homeostasis and its ability to influence signal transduction pathways to promote growth [9,10]. Although most tissues can synthesize glutamine, during periods of rapid growth or other stresses, demand outpaces supply, and glutamine becomes conditionally essential particularly in cancer cells, many of which display oncogene-dependent “glutamine addiction” in culture [11]. Although it supports energy production in proliferating normal cells and cancer cells, recent research opposes the diction that glutamine is just a “fuel” for cell growth. There is accumulating evidence that glutamine is a multi-functional regulator of several activities and thus a signaling molecule [3,12]. These interactions highlight the complex interplay between glutamine metabolism and many aspects of cell biology.