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  • br Materials and methods br Results br Discussion Directly m

    2021-10-13


    Materials and methods
    Results
    Discussion Directly modulating specific target proteins and signaling pathways with small-molecule drugs or agonistic GNE-317 sale is widely used for cancer metastasis therapies [[39], [40], [41]]. ANXA7 acts as a metastasis suppressor in prostate cancer. However, the mechanism of ANXA7 on inhibiting prostate cancer metastasis is not clear. In the current study, we revealed for the first time that activation of ANXA7 GTPase by SEC increases AMPK phosphorylation to suppress mTORC1/STAT3 signal pathway and to compromise the expression of pro-metastatic genes—CCL2, APLN and IL6ST, leading to the inhibition of prostate cancer metastasis. The binding of RKIP to ANXA7 is the critical point that blocked SEC-induced ANXA7 GTPase activation and its downstream signaling pathway (Fig. 9). AMPK is an evolutionally conserved energy sensor across various species from yeast to mammal [42,43]. AMPK could recede disordered cellular metabolism in cancers and inhibited tumorigenesis and development by controlling proliferation, autophagy and migration [44,45]. It has been reported that AMPK activators, such as antroquinonol,metformin and A-769662, could suppress the deterioration of prostate cancer, breast cancer, ovarian cancer and lymphoma [46]. Metformin targets c-MYC oncogene to prevent prostate cancer and is also able to decrease the risk of certain cancers induced by type II diabetes cancer [47,48] Several GTPases are able to regulate AMPK activity, including the activation of AMPK by Rab13 and Rheb [49,50], and the inhibition of AMPK by SPAG-1 [51]. Our previous work demonstrated that ANXA7 GTPase could regulate its interactive protein phosphorylation [10]. Herein, we focused on the effect of ANXA7 on AMPK phosphorylation. Co-immunoprecipitation assay showed that SEC enhanced the binding of ANXA7 to AMPK and increased AMPK phosphorylation. To further investigate the effect of ANXA7 GTPase on AMPK phosphorylation, we constructed mCherry-ANXA7-mt3 (T286D), a dominant-active mutant of ANXA7 GTPase. Compared with mCherry-ANXA7-wt transfection, overexpression of mCherry-ANXA7-mt3 (T286D) increased AMPK phosphorylation. These results indicate that SEC enhanced ANXA7 GTPase activity, which subsequently activated AMPK. In addition to the intended target, compounds are possible to bind to off-target molecules, thereby causing beneficial or side effects [52,53]. Whether the off-target effect of SEC enhances or attenuates SEC efficiency needs further investigation. AMPK is a serine/threonine protein kinase and suppressed mTORC1 activity by promoting the phosphorylation of TSC2 and raptor [[54], [55], [56]]. AMPK/mTOR signaling-mediated anoikis resistance and autophagy induction participated in the metastasis regulation of various cancers [57,58]. Here, we discovered that SEC downregulated the expression of CCL2, APLN and IL6ST, which play a critical role in promoting cancer metastasis [[24], [25], [26], [27], [28]]. In addition, CCL2, APLN and IL6ST are STAT3 GNE-317 sale target genes and the expression of the three pro-metastatic genes is controlled by STAT3 [29,30]. STAT3 functions at the downstream of mTORC1. The phosphorylation of STAT3 at Ser727 and Tyr705 triggers STAT3 dimerization, induces STAT3 nuclear translocation and promotes the binding of STAT3 to its target gene promoters [35,36,59]. Our current study elucidated that SEC inhibited mTORC1 activity, decreased the phosphorylation of STAT3, and blocked STAT3 nuclear translocation. Therefore, our new findings suggest that SEC activates ANXA7 GTPase and decreases the expression of CCL2, APLN and IL6ST, consequently leading to the inhibition of metastasis. In addition, ITGB4 located on membrane could bind to PI3K and activate AKT/mTOR signaling, which promotes glioma metastasis [60]. Our previous study has demonstrated that SEC could induce ITGB4 nuclear translocation. Therefore, we reason that ITGB4 nuclear translocation may inhibit mTOR activity and suppress metastasis.