Huaier aqueous extract sensitizes cells to rapamycin and cisplatin through activating mTOR signaling
Graphical abstract
Introduction
The mechanistic target of rapamycin (mTOR) signaling pathway is aberrant in various human diseases, including cancer, depression, obesity, and diabetes (Betz and Hall, 2013, Laplante and Sabatini, 2012). mTOR is a serine/threonine protein kinase, specifically inhibited by rapamycin. mTOR regulates cell proliferation, differentiation, apoptosis, protein translation, and energy metabolism (Hay and Sonenberg, 2004, Jewell et al., 2015, Shimobayashi and Hall, 2014, Showkat et al., 2014). TSC1 (tuberous sclerosis 1) and TSC2 (tuberous sclerosis 2) are both tumor suppressor genes, located in the upstream of mTOR. Mutational inactivation of TSC1 or TSC2 cause mTOR activation, resulting in tuberous sclerosis complex (TSC) (Crino et al., 2006, Inoki et al., 2002, Zhang et al., 2003). Rapamycin and its derivatives are regarded as the ideal curative drugs for cancers driven by activation of mTOR. Nevertheless, the therapeutic effect of rapamycin is not so good because of giving rise to activation of AKT, infection, and drug dependence (Bissler et al., 2008, Franz et al., 2006, McCormack et al., 2011, Zhang et al., 2007, Zhang et al., 2003). Thus, it is needful and valuable to develop new therapeutic drugs against cancers with dysfunctional mTOR signaling, including tuberous sclerosis complex.
The research of anti-cancer Traditional Chinese Medicine (TCM) are promising recently. TCM are multi-target drugs that improve immune function and kill tumor cells. Moreover, TCM have long-lasting anti-tumor effect and low recurrence rate. Clinically, TCM as adjuvant drugs of chemoradiotherapy in the treatment of cancers have excellent efficacy (Efferth et al., 2007, Wang et al., 2014). Trametes robiniophila Murr. (Huaier) is a medicinal fungus for treatment of inflammation and cancer in China, used for more than 1600 years in Traditional Chinese Medicine (Yi, 1993). Huaier Granule has good clinical effect in various types of cancers, such as liver cancer, lung cancer, gastric cancer, and breast cancer. Huaier Granule alone or in combination with other drugs could improve the life quality of patients and prolong the patient's survival time. Huaier aqueous extract mainly contains proteoglycans, proteins and minerals. Recently, studies on chemical separation and pharmacology show that effective ingredients of Huaier aqueous extract are proteoglycans (Guo Yuewei et al., 1992, Guo et al., 1993). The underlying mechanism of anti-neoplastic effect of Huaier remains poorly understood.
In this study, we demonstrated that activation of mTOR sentisized cells to Huaier treatment. Huaier inhibits tumorigenesis of cells with activated mTOR. Moreover, Combination of Huaier and rapamycin or cisplatin led to a further reduction of cell viability compared with rapamycin or cisplatin alone. In addition, Huaier treatment upregulated mTOR signaling. Huaier alone or in combination with rapamycin may be a candidate strategy for the treatment of cancers caused by aberrant mTOR signaling.
Section snippets
Cell culture
Tsc1+/+ MEFs, Tsc1ā/ā MEFs, Tsc2+/+ MEFs, Tsc2ā/ā MEFs, and Ptenā/ā MEFs have been described previously (Kwiatkowski et al., 2002, Ma et al., 2010, Zhang et al., 2003). Human hepatoma cell lines SKHEP-1, HepG2, and human lung carcinoma cell line A549 are from American Type Culture Collection. Cells were cultured in Dulbeccoās Modification of Eagleās Medium (DMEM) with 10% fetal bovine serum (FBS) and 1% penicillin-streptomycin at 37Ā Ā°C and 5% CO2. ELT3 cells (TSC2-deficient Eker rat uterine
Huaier inhibits proliferation of human cancer cells in vitro
To expore the effect of Huaier on the proliferation of human cancer cells, we treated human hepatoma cell line SKHEP-1 and human lung carcinoma cell line A549 with the indicated concentrations (0, 2, 4, 6, 8Ā mg/ml) of Huaier extract for different time periods (24, 48, 72Ā h). As shown in Fig. 1A and B, the cell viability of SKHEP-1 and A549 cells were significantly reduced by Huaier extract in a dose-dependent manner.
Huaier inhibits proliferation and tumorigenesis of cells with activated mTOR
Cells with activated mTOR are more sensitive to rapamycin treatment in comparison
Discussion and conclusion
In this study, we have demonstrated that Huaier extract has remarkable proliferation inhibition effect on human cancer cells. Activation of mTOR sensitizes cells to Huaier treatment. Huaier suppresses tumorigenic capacity of cells with activated mTOR. Moreover, Huaier augments the sensitivity of cells to rapamycin and cisplatin, which may be caused by activation of mTOR signaling pathway induced by Huaier.
Cancer treatment with TCM has been demonstrated to be significant and attracted increasing
Conflict of interest
None.
Acknowledgments
This study was financially supported by the National Natural Science Foundation of China (81403147) and grants from Beijing University of Chinese Medicine (2015-JYB-XYQ-004, 2014-JYBZZ-JS-024).
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These authors contributed to this work equally.