SEC-induced activation of ANXA7 GTPase suppresses prostate cancer metastasis

Abstract

Annexin A7 (ANXA7) is a suppressor of tumorigenesis and metastasis in prostate cancer. Activated ANXA7 GTPase promotes prostate cancer cell apoptosis. However, the role and underlying mechanism of ANXA7 GTPase in prostate cancer metastasis have not been established. RKIP is a metastatic suppressor and downregulated in prostate cancer metastases. The binding of RKIP and its target proteins could inhibit the activation of its interactive partners. However, the effect of RKIP on ANXA7 GTPase activation is not clear. Here, we report that activation of ANXA7 GTPase by a small molecule SEC ((S)-ethyl 1-(3-(4-chlorophenoxy)-2-hydroxypropyl)-3- (4-methoxyphenyl)-1H-pyrazole-5-carboxylate) effectively inhibited prostate cancer metastasis. Mechanistically, activated ANXA7 promoted AMPK phosphorylation, leading to decreased mTORC1 activity, suppressed STAT3 nuclear translocation, and downregulation of pro-metastatic genes, including CCL2, APLN, and IL6ST. Conversely, RKIP interacted with ANXA7 and impaired activation of ANXA7 GTPase by SEC and its downstream signaling pathway. Notably, SEC treatment suppressed metastasis of prostate cancer cells in in vivo orthotopic analysis. Together, our findings provide a novel insight into how metastasis of prostate cancer with low RKIP expression is suppressed by SEC-induced activation of ANXA7 GTPase via the AMPK/mTORC1/STAT3 signaling pathway.

Exopolysaccharides isolated from Rhizopus nigricans induced colon cancer cell apoptosis in vitro and in vivo via activating the AMPK pathway

“…AMPK activation may serve to alleviate disordered cellular metabolism in cancers cells and suppress tumorigenesis by inhibiting cellular proliferation and simultaneously inducing apoptosis in tumor cells. AMPK has, therefore, been proposed as a therapeutic approach to decrease tumorigenesis [17,42,43].…”

“…Importantly, AMPK also plays a vital role in the induction of apoptosis in various types of cancer cells [16]. Liu et al [17] reported that SEC-induced activation of Annexin (ANXA7) GTPase inhibits prostate cancer metastasis through AMPK activation. Moreover, a recent paper revealed that berberine regulates AMPK signaling pathways and suppresses colon tumorigenesis in azoxymethane/dextran sulfate sodium (AOM/DSS)-induced CRC mice [18].…”

Promoting TTC4 and HSP70 interaction and translocation of annexin A7 to lysosome inhibits apoptosis in vascular endothelial cells

“…47 And another small molecular (S)-ethyl 1-(3-4-2-hydroxypropyl)-3-(4methoxyphenyl)-1H-pyrazol-5-carboxylate (SEC) that could activate the GTPase activity. 27 ABO and SEC bound to the same site of ANXA7. Thus, we reason that ABO may promote the interaction of HSP70 and TTC4 and SEC may inhibit this effect in VEC apoptosis.…”

“…In glioblastoma, melanoma and prostate cancer, ANXA7 acts as a tumor suppressor. [25][26][27] In liver cancer, colorectal cancer and breast cancer, ANXA7 may promote tumor metastasis by regulating cell migration. [28][29][30] In our previous studies, we demonstrated that two small molecules 6-amino-2, 3-dihydro-3-hydroxymethyl-1, 4-benzoxazine (ABO), and (S)-ethyl 1-(3-(4-chlorophenoxy)-2-hydroxypropyl)-3-(4-methoxyphenyl)-1H pyrazol-5-carboxylate (SEC) targeted ANXA7 GTPase activity.…”

“…[28][29][30] In our previous studies, we demonstrated that two small molecules 6-amino-2, 3-dihydro-3-hydroxymethyl-1, 4-benzoxazine (ABO), and (S)-ethyl 1-(3-(4-chlorophenoxy)-2-hydroxypropyl)-3-(4-methoxyphenyl)-1H pyrazol-5-carboxylate (SEC) targeted ANXA7 GTPase activity. 22,27 Inhibiting ANXA7 GTPase by ABO could suppress VEC apoptosis induced by deprivation of serum and FGF-2. 31 SEC promoted VEC apoptosis by stimulating ITGB4 nuclear translocation.…”