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  • ω-Agatoxin TK sale br Materials and Methods br Results br

    2022-11-17


    Materials and Methods
    Results
    Discussion XHP is a traditional Chinese anti-cancer medicine that is widely used for the treatment and adjuvant treatment of breast cancer. XHP has been shown to induce apoptosis in various breast cancer ω-Agatoxin TK sale in vitro, including Hs578T, MCF-7, and MDA-MB231 cell lines [11,13]. In this study, we established a 4T1 mouse breast cancer model and treated the mice with XHP for 2 weeks. We showed that XHP decreased the weight of tumors in the model mice in a dose-dependent manner, indicating that XHP could inhibit the growth of 4T1 breast tumors. Many reports have shown increases in the number and proportion of Treg cells in the tumor microenvironment in breast cancer patients. This increase in Treg cells could weaken the body’s anti-tumor immune function and promote the development of breast cancer [[22], [23], [24], [25], [26], [27]]. Tiriveedhi et al. [42] treated breast cancer patients with Mam-A cDNA vaccine and found that it could reduce the number of Treg cells in the peripheral blood, enhance the body’s anti-tumor immune response, and inhibit the growth of breast cancer. Another study showed that the number of Treg cells in the peripheral blood of breast cancer patients was significantly decreased by treatment with a CD25 monoclonal antibody, while the patient’s own anti-tumor immune function was restored, and breast cancer growth was inhibited [43]. Although these studies suggest that reducing the number of Treg cells in the peripheral blood could enhance the antitumor immune response in patients with breast cancer, changes in Treg cells in the peripheral blood do not directly reflect changes in Treg cells in the tumor microenvironment. In this study, we detected the effects of XHP on Treg cells in the tumor microenvironment in 4T1 breast cancer model mice by flow cytometry and immunohistochemistry. The results showed that XHP dose-dependently reduced Treg cells in the tumor microenvironment in this model, suggesting that XHP improved antitumor immune function and inhibited the growth of 4T1 breast cancer by reducing the number of Treg cells in the tumor microenvironment. We clarified the specific mechanism whereby XHP promoted Treg cell apoptosis by examining its effect on expression of the MEKK1/SEK1/JNK1/AP-1 pathway, as an important component of the TCR signaling pathway [[28], [29], [30]]. Activation of this signaling pathway is involved in promoting T cell apoptosis [[30], [31], [32], [33]]. Suddason et al. showed that knockout of the MEKK1 gene in mice resulted in a constant increase in invariant natural killer T, CD4 +, and CD8 + T cells in the liver and spleen, which could be related to the ability of MEKK1 to promote apoptosis of T cells [44]. Another study showed that MEKK1 promoted the activation and transcription of the FasL promoter in Jurkat T lymphocytes and induced Fas–FasL-mediated apoptosis of T cells [31]. MEKK1 activation has also been shown to activate SEK1 [34], which can in turn promote T cell apoptosis by activating the JNK apoptosis signaling pathway [33,38]. Rincón et al. established a mouse model lacking JNK1 activity, and found that JNK1 activation promoted TCR-induced apoptosis of CD4+ CD8 + T cells in the thymus [32,37]. In addition, JNK1 activation also occurred during the early stage of apoptosis in Jurkat T cells induced by γ- and ultraviolet radiation, which could promote Fas–FasL-mediated T cell apoptosis by up-regulating the expression of FasL in T cells [35,45,46]. Activation of JNK has also been shown to contribute to the apoptosis of Jurkat T cells induced by TRAIL and major histocompatibility complex I [36,47]. Activated JNK can also translocate to the nucleus to activate the nuclear transcription factor AP-1 (c-Jun) [39], which can then bind to DNA in the T cell nucleus and promote the transcription of apoptosis-related genes such as FasL and Bim, which in turn induce apoptosis of T cells [30,40,41,[48], [49], [50]]. These studies indicated that increased expression of MEKK1, SEK1, JNK1, and AP-1 could promote T cell apoptosis; however, there are currently no relevant results to demonstrate that increases in MEKK1, SEK1, JNK1, and AP-1 proteins promote apoptosis in Treg cells. In this study, we showed that XHP upregulated both mRNA and protein expression levels of MEKK1, SEK1, JNK1, and AP-1 in Treg cells in the tumor microenvironment in a 4T1 breast cancer mouse model using RT-qPCR, and immunofluorescence and western blot, respectively. In addition, TUNEL staining revealed that XHP promoted the apoptosis of Treg cells in the tumor microenvironment in 4T1 breast cancer model mice.