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  • Hinokitiol has versatile abilities as anticancer antimicrobi

    2020-10-22

    Hinokitiol has versatile abilities as anticancer, antimicrobial and molecule transport agents and appears to have no developmental toxicity or carcinogenic effects (Imai et al., 2006b). For anticancer activities, it causes apoptosis and PTC-209 receptor arrest in many different types of cancers, such as murine embryonal carcinoma cells, murine lymphocytic leukemia cells and prostate cancer cells (Ido et al., 1999; Liu and Yamauchi, 2006; Morita et al., 2004). In our present study, hinokitiol exhibited apoptosis effects (Fig. 1A, D) possibly through its suppression of survivin expression in melanoma B16-F10 cells (Fig. 2). In addition, our findings concluded that hinokitiol suppressed survivin expression via ERK/MKP-3/proteosome pathway and suppressed the colony formation of melanoma B16-F10 cells. Hinokitiol possesses potent anti-tumor effects by inducing cell apoptosis (Seo et al., 2017). Our present study also demonstrated that hinokitiol induced apoptosis effects (Fig. 1A, D) possibly through suppression of survivin expression in melanoma B16-F10 cells (Fig. 2). Increased expression of survivin is associated with tumor cell proliferation, progression, therapeutic resistance and poor prognosis (Khan et al., 2017), hence the suppression of survivin can inhibit melanoma growth in vitro (Grossman et al., 2001; Kedinger et al., 2013). This notion is substantiated by the finding that survivin can activate phosphatidylinositol 3-kinase (PI3K)/Akt and Akt/glycogen synthase kinase-3 (GSK-3β)/β-catenin pathways, resulting in cell survival and anti-apoptosis in malignant myeloid leukemia and breast cancer cells (Oh et al., 2017; Serrano-López et al., 2013). We demonstrated a new mechanism of hinokitiol on ERK/MKP-3/survivin pathway in metastatic melanoma B16-F10 cells. Thus, findings of hinokitiol-inhibition of survivin may shed some light on a novel approach for melanoma therapy. ERK signaling pathway plays a PTC-209 receptor central role in tumor growth behaviors including invasion, metastasis and survival, because metastatic melanoma exhibits a high degree of mutation in both Ras and BRAF, exerting oncogenic effects by activating ERK signaling pathway. In fact, inhibition of ERK activity or functional suppression of Ras and BRAF kinase activity has been a clinically important strategy in treatment of melanoma; however, the drug therapy for metastatic melanoma with mutation of Ras and BRAF have failed in many patients because of transient responses and rapid resistance to these melanoma treatments. Inhibition of Ras or BRAF kinase is able to decrease ERK activity leading to suppression of melanoma growth, while re-establishment of ERK activity in drug-resistant melanoma may recover its growth ability (Wellbrock and Arozarena, 2016), suggesting that regulation of ERK signaling pathway can critically affect treatment of melanoma. This notion was supported by our findings that exposure of B16 melanoma cells to hinokitiol induced a transient increase followed by a sustained decrease in ERK phosphorylation (Fig. 5). More importantly, hinokitiol-induced expression of MKP-3 was dependent on ERK activity while inhibition of subsequent ERK activity was in turn dependent on MKP-3 activity (Fig. 6B). These results indicated that hinokitiol was able to sequentially activate ERK and MKP-3 to suppress cell growth in B16 melanoma. MKP-3, a dual phosphatase, can specificity dephosphorylate phosphotyrosine and phosphothreonine within ERK, thus increased MKP-3 expression is able to negatively regulate ERK signaling in mammalian cells. MKP-3 exhibits distinct effect on different mammalian cells; for example, increased expression of MKP-3 by genetic method can inhibit growth of human melanoma cell line while promoting formation of tumor in tumourigenic mouse melanocyte (Ahmad et al., 2018). Our results revealed that hinokitiol induced ERK activity-dependent MKP-3 expression which in turn inhibits ERK activity, and the inhibition was closely associated with downregulation of survivin protein and inhibition of cell growth in B16 melanoma (Fig. 8). Previous study has showed that phosphorylation of survivin by ERK can increase its post-translational stability and decrease its proteosome degradation in pancreatic β-cell (Wang et al., 2010). Disruption in phosphorylated site Thr34 of survivin by genetic method can induce apoptotic cell death and inhibit cell growth in human melamoma cell line (Grossman et al., 2001). These observations implied that modification of phosphorylation of survivin by protein kinase can critically affect its functions in inhibition of apoptosis and post-traslational stability. We further found that hinokitiol-induced increase in ubiquitination and downregultion of survivin could be inhibited by MKP-3 inhibitor NSC 95397 (Fig. 8A and C); furthermore, inhibition of MKP-3 activity could significantly attenuate hinokitiol-induced inhibition in cell migration (Fig. 9A and B), suggesting that MKP-3-mediated ERK inactivation and survivin downregulation also play an important role in inhibition of cell migration induced by hinokitiol in B16 melanoma. These results implied that increased expression and activity of MKP-3 was closely correlated with the reduction in expression and post-translational stability of survivin and migration inhibition induced by hinokitiol in B16 melanoma.