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  • br Conflict of interest br Acknowledgements This work was su

    2019-07-13


    Conflict of interest
    Acknowledgements This work was supported in part by JSPS KAKENHI Grant Number 26292031. We thank Nissan Chemical Industries, Ltd. for the gift of the sample of fluralaner.
    Introduction As one of the most common cancers in southern China and southeast Asia, nasopharyngeal carcinoma (NPC) presents a severe health problem in southern China, in which it has an annual incidence of 15–50 cases per 100,00 individuals [1] With the popularity of intensity-modulated radiation therapy and concurrent chemo-radiation therapy, many improvements have been made in treatments that exert local and regional control in NPC patients with locoregionally advanced disease. However, the prognosis is still undesirable due to recurrence and distant metastasis [2]. NPC is highly invasive in the late stages but is rarely detected during regular medical examinations due to its unique location and lack of specific symptoms [3]. The carcinogenesis of NPC is thought to be associated with complex interactions among genetic, viral, environmental, and dietary factors. The molecular pathogenesis of NPC includes the altered expression and function of multiple genes (e.g., dominant oncogenes, recessive oncogenes or tumor-suppressor genes) and signaling pathways [4]. Increasing our understanding of the molecular mechanisms underlying NPC is essential to the development of new effective therapeutic agents. Endoplasmic reticulum (ER) functions that respond to cellular perturbations are critical to the survival of cells. Unfolded and misfolded proteins accumulate in the ER lumen under a number of cellular stress conditions, including nutrient deprivation, oxidative stress, hypoxia, glycosylation alteration, and calcium flux disturbance, leading to what is referred to as ER stress. Caused by the activation of the unfolded protein response (UPR) in stressed cells, ER stress results from the perturbation of ER functions or homeostasis. The UPR is primarily transduced by three ER-resident sensor proteins, including protein kinase R–like ER kinase, activating transcription factor 6α, and inositol-requiring enzyme 1α. Recently, the URP has repeatedly been demonstrated to be important and necessary for tumor mitotic inhibitors to maintain malignancy and therapy resistance [5]. Under continued and severe ER stress, the UPR induces cell-death programs, thereby dispensing the stressed cells. As unfolded proteins accumulate, the ER chaperone protein immunoglobulin heavy-chain-binding protein (GRP78) is expressed at increasingly high levels and becomes dissociated from the ER receptors. In a variety of cancer cells and solid tumours (breast, lung, prostate and ovarian cancers, melanoma, and glioma cells), the level of GRP78 expression is highly induced and could be essential for the survival of stressed cells such as cancer cells [[6], [7], [8]]. This process activates the receptors and triggers the ER stress response. The ATF4 protein has been shown to be present at higher levels in cancer tissues than in normal tissues, and it is upregulated by tumor microenvironment signals, such as oxidative stress, hypoxia/anoxia and ER stress [9]. In response to ER stress, the expression of the transcription factor CCAAT-enhancer-binding protein homologous protein (CHOP), a major inducer of apoptosis, also increases [10]. There are many volume-regulated ion channels involved in or regulating tumor cell apoptosis, for instance, the transient receptor potential vanilloid channel 4 (TRPV4) [8,11], chloride channels [12]. Chloride channels have been demonstrated to be critical factors in the regulation of the cell cycle and cell proliferation [13,14]. There are six main types of chloride channels, which belong to the CLC superfamily of voltage-gated chloride channels. It has been reported that apoptotic stimuli, including both mitochondrion-mediated intrinsic stimuli and death receptor-mediated extrinsic stimuli, can rapidly activate VSOR Cl− conductance in various types of cells [[15], [16], [17]]. The VSOR Cl− channel plays a key role in the occurrence of apoptosis by inducing apoptotic volume decrease (AVD), a major hallmark of cell apoptosis and an early prerequisite to apoptotic events. Observed soon after cell swelling, regulatory volume decrease (RVD) is completed by the parallel activation of VSOR Cl− channels in numerous cell types [18,19]. In addition,. The involvement of Cl− channels regulatory mechnism in apoptosis has been suggested in many cell types. Various Cl− channel blockers displayed either an inhibitory effect on apoptosis. Thus, the non-swelling-coupled activation of VSOR Cl− channels is believed to cause AVD in many cells [20,21]. The prevention of AVD helps various types of cells evade subsequent biochemical and morphological apoptotic events and rescues cells from death [22,23]. According to previous studies, inhibiting VSOR Cl− channels could suppress apoptotic events [24,25].