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    • Annexin A ANXA a member

    2021-10-15

    Annexin A7 (ANXA7), a member of annexin superfamily, is a Ca2+- and phospholipid-binding protein and possesses GTPase activity [5,6]. The ANXA7 gene is located on human chromosome 10q21, where multiple potential tumor suppressor genes exist. Homozygous ANXA7 (−/−) knockout mice showed a lethal phenotype at embryonic day 10 [7]. Heterozygous ANXA7 (±) knockout mice have a high frequency of spontaneous tumors (about 20–50%) in multiple organs, including liver, prostate, endometrium, salivery gland and thymus [8]. Moreover, tumor metastasis was observed in 42% of the mutant mice developing spontaneous tumor [8]. These findings suggest that ANXA7 may play an important role in inhibiting tumorigenesis and metastasis. Compared with that in normal and healthy prostate tissue, ANXA7 SKF 96365 hydrochloride is reduced by approximately 50% in primary prostate tumors and even more downregulated in metastatic prostate cancers [7,9]. However, the mechanism of ANXA7 GTPase in the regulation of metastasis has not been established. Our recent work has demonstrated that activation of ANXA7 GTPase by a small molecule SEC ((S)-ethyl 1-(3-(4-chlorophenoxy)-2-hydroxypropyl)-3-(4-methoxyphenyl)-1 H-pyrazole-5 -carboxylate) induces prostate cancer cell apoptosis [10]. We wondered whether activated ANXA7 GTPase could inhibit prostate cancer metastasis. Raf kinase inhibitory protein (RKIP) has been associated with natural anti-metastasis property in multiple tumor types [11]. The metastatic suppression role of RKIP was initially identified in prostate cancer [12]. RKIP expression is low in metastatic prostate cancer cell lines PC3 and DU145, while RKIP is relatively high expressed in non-invasive prostate cancer cell line LNCaP [13]. Analysis of clinical samples showed that metastases of human prostate cancer exhibited dramatically decreased RKIP level compared with benign prostate hyperplasia and localized prostate cancer samples [12,13]. It has been proposed that low RKIP expression is a good prognostic marker for the pathogenesis of human prostate cancer [14]. Accumulating evidence suggests that RKIP associates with GTP-binding proteins [15]. RKIP associates with Raf-1 and inhibits the Raf/MEK/ERK/Myc signaling, leading to the inhibition of Snail and TET activity and decreased pro-metastatic gene expression [16]. RKIP interferes with NF-κB signaling by the interaction with several upstream kinases TAK1, NIK and IKK, contributing to metastasis inhibition [17]. The binding of RKIP and its target proteins could inhibit the interactive proteins activation by their activators, leading to the inversion of related signaling and the inhibition of tumor metastasis [18]. In addition, it was reported that nonylphenol induced the upregulation of RKIP in testicular Sertoli cells, accompanied with decreased ANXA7 protein level [19]. However, the role and mechanism of RKIP in the regulation of ANXA7 signaling pathway remains unknown so far. We seek to determine whether RKIP binds to ANXA7 and antagonizes the activation of ANXA7 GTPase by SEC. In the current study, we used metastatic prostate cancer cell PC3 as well as non-metastatic LNCaP, and constructed HEK293T RKIP−/− cell line, together with HEK293T RKIP+/+ cell line as the cell model, to study the role and mechanism of ANXA7 GTPase in prostate cancer metastasis. Our substantial evidence suggests that SEC treatment increases AMPK phosphorylation via activating ANXA7 GTPase, and that activated AMPK inhibits STAT3 nuclear translocation via the mTORC1/STAT3 pathway, leading to downregulation of pro-metastatic genes and inhibition of prostate cancer metastasis. Notably, RKIP interacts with and compromises the inhibitory effect of SEC on prostate cancer metastasis. Together, our findings indicate that activation of ANXA7 by a small molecule SEC antagonizes prostate cancer metastasis with low RKIP expression via the AMPK/mTORC1/STAT3 signaling pathway, providing a novel insight into how prostate cancer metastasis is suppressed by a small molecule SEC via previously uncharacterized but essential interplay between the two metastasis suppressors ANXA7 and RKIP.