SEC Induces Activation of ANXA7 GTPase and Promotes Apoptosis

The major cause of cancer mortality is cancer metastasis, which accounts for approximately 90% of deaths. As we all know, most primary tumors are manageable or curable. However, once cancer cells leave and spread beyond their primary site, they become incurable and fatal.
Annexin A7 (ANXA7) is a member of the Annexin superfamily. It is also a Ca2+– and phospholipid-binding protein and possesses GTPase activity. ANXA7 is highly expressed in 42% of the mutant mice developing spontaneous tumors. As a result, ANXA7 may exert an important role in inhibiting tumorigenesis and metastasis.

In this article, we will introduce a small molecule, SEC.

SEC induces activation of ANXA7 GTPase via the AMPK/mTORC1/STAT3 signaling pathway. Besides, in a cell viability assay, SEC inhibits the cell migration of HEK 293T RKIP−/− cells and PC3 prostate cancer cells. However, it does not affect HEK293T RKIP+/+ cells.
Additionally, in PC3 cells, SEC significantly increases AMPK phosphorylation. It can invert the p-AMPK decrease induced by ANXA7 GTPase-specific inhibitor ABO. This result shows that activated-ANXA7 with enhanced phosphorylation level promotes AMPK phosphorylation (cell selectively).

In a nude mice model with Luciferase-labeled PC-3M-Luc cells. SEC suppresses metastasis in this PC-3M-Luc orthotopic implantation nude mice model. It suppresses the lymph node metastatic capacities of PC-3M-Luc cells. And it decreases the mRNA level of CCL2, APLN, and IL6ST in implanted tumors. Furthermore, SEC does not affect the bodyweight of the mice.

ANXA7 is a metastasis suppressor in prostate cancer, but the mechanism of ANXA7 on inhibiting prostate cancer metastasis is not clear. The binding of RKIP to ANXA7 is the critical point for the SEC-induced-ANXA7 signal pathway. At the same time, It compromises the expression of pro-metastatic genes—CCL2, APLN, and IL6ST, leading to the inhibition of prostate cancer metastasis.

[1]. ShuYan Liu, et al. Cancer Lett. 2018 Mar 1;416:11-23.