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  • Cantharidin is a natural element extracted from blister


    Cantharidin is a natural element extracted from blister beetles, and has been proven to be effective in cancer [16]. NCTD, the demethylated analog of cantharidin, has been synthesized and been shown to have an equal anti-cancer effect with fewer side effects than cantharidin [39]. It was confirmed that NCTD suppresses cell proliferation, cell migration and invasion, and induces cell apoptosis, apiii arrest and cell senescence in several cancers, including breast cancer [[40], [41], [42], [43]]. Previous data have shown that NCTD suppresses the growth of MDA-MB-231 (ER-/PR-/HER2-), a TNBC cell line [28]. Due to the lack of a therapeutic target, TNBC is more aggressive and has a worse prognosis than other subtypes of breast cancer [3]. In this study, the results showed that NCTD more effectively suppressed the proliferation of TNBC cells compared with non-TNBC cells, indicating that NCTD may act as a potential adjuvant treatment in TNBC. However, the underlying mechanism is unclear. It has been confirmed that the inhibition of Akt or ERK signaling is closely related to cell proliferation, cell cycle distribution, invasion and metastasis in several cancers, including breast cancer [[8], [9], [10], [11],13]. In recent years, small molecule inhibitors targeting the pAkt or pERK1/2 signaling pathways have been shown to effectively attenuate tumor cell proliferation and invasion, and induce cell cycle arrest, cell apoptosis and even cell senescence [12,44]. However, the effect, especially that of ERK inhibitors in TNBC, is limited. This may be related to the relatively low level of phosphorylated ERK in TNBC [45]. Akt inhibitors have a better effect, which is probably due to the level of phosphorylated Akt being significantly higher in TNBC than in non-TNBC [46]. Furthermore, NCTD suppressed cell proliferation, angiogenesis, epithelial-mesenchymal transition and induced cell apoptosis by blocking ERK signaling in colon cancer and hepatoma [20,47,48]. NCTD also inhibited cell proliferation, angiogenesis, metastasis and overcame drug-resistance by targeting Akt signaling in several cancers [19,28]. Moreover, it has been widely reported that crosstalk exists between the Akt and ERK signaling pathways, and inhibition of one pathway leads to enhanced activation of the other, which may weaken their anti-tumor effect and result in drug resistance [[49], [50], [51]]. Therefore, dual inhibition of Akt and ERK signaling might result in better tumor inhibition in TNBC [52]. However, little is known about the effect of NCTD on both Akt and ERK signaling in cancers, especially in TNBC. In this study, NCTD simultaneously inhibited Akt and ERK signaling both in vitro and in vivo. The potential crosstalk between these two signaling pathways was observed when either LY294002 or U0126 was used, which partly explains the ineffectiveness or drug resistance of single inhibition in some studies [[49], [50], [51]]. It is worth mentioning that further studies are required to determine the detailed mechanism between Akt and ERK signaling in NCTD-induced tumor suppression. Cell senescence is the biological response to abnormal extracellular or intracellular stress. Its tumor-suppressive function has been confirmed, since it blocks tumor cells at a certain phase of cell cycle, thereby decreasing cell proliferation [36]. It has been widely confirmed that Akt or ERK signaling is closely related to cell senescence in several cancers, including breast cancer [[11], [12], [13]]. However, no study has shown that dual inhibition of Akt and ERK signaling significantly induces cell senescence in cancer. Also there are no data to show that NCTD induces cell senescence in breast cancer. In this study, the results showed that NCTD induced cell senescence in TNBC by mainly targeting Akt and ERK apiii signaling. However, recent studies have revealed the two sidedness of cell senescence [37]. SASP cells secrete a series of soluble signaling factors, such as interleukins, inflammatory cytokines and growth factors, which affect the surrounding environment and consequently change cell behavior. Numerous studies have reported that SASP promotes cell proliferation and cell motility in several cancers, including breast cancer [[53], [54], [55]]. Our data indicate that NCTD induces TNBC cell cycle arrest and cell senescence, while also upregulating the level of soluble signaling factors of SASP in a NF-κB-independent manner. However, luciferase activity was significantly decreased under Akt and ERK inhibitors treatment, accompanied by a decrease of the majority of these SASP-related genes. Whether this will weaken or even reverse the anti-cancer effect of NCTD requires further research.