Annexin A2 (ANXA2) orchestrates multiple biologic processes and clinical associations, especially in cancer progression. The structure of ANXA2 affects its cellular localization and function. However, posttranslational modification and protease-mediated N-terminal cleavage also play critical roles in regulating ANXA2. ANXA2 expression levels vary among different types of cancers. With some cancers, ANXA2 can be used for the detection and diagnosis of cancer and for monitoring cancer progression. ANXA2 is also required for drug-resistance. This review discusses the feasibility of ANXA2 which is active in cancer development and can be a therapeutic target in cancer management.

Cancer metastasis accounts for the major cause of cancer-related deaths. How disseminated cancer cells cope with hostile microenvironments in secondary site for full-blown metastasis is largely unknown. Here, we show that AMPK (AMP-activated protein kinase), activated in mouse metastasis models, drives pyruvate dehydrogenase complex (PDHc) activation to maintain TCA cycle (tricarboxylic acid cycle) and promotes cancer metastasis by adapting cancer cells to metabolic and oxidative stresses. This AMPK-PDHc axis is activated in advanced breast cancer and predicts poor metastasis-free survival. Mechanistically, AMPK localizes in the mitochondrial matrix and phosphorylates the catalytic alpha subunit of PDHc (PDHA) on two residues S295 and S314, which activates the enzymatic activity of PDHc and alleviates an inhibitory phosphorylation by PDHKs, respectively. Importantly, these phosphorylation events mediate PDHc function in cancer metastasis. Our study reveals that AMPK-mediated PDHA phosphorylation drives PDHc activation and TCA cycle to empower cancer cells adaptation to metastatic microenvironments for metastasis.

Summary The inflammatory effects of glycogen synthase kinase‐3 (GSK‐3) have been identified; however, the potential mechanism is still controversial. In this study, we investigated the effects of GSK‐3‐mediated interleukin‐10 (IL‐10) inhibition on lipopolysaccharide (LPS)‐induced inflammation. Treatment with GSK‐3 inhibitor significantly blocked LPS‐induced nitric oxide (NO) production as well as inducible NO synthase (iNOS) expression in BV2 murine microglial cells and primary rat microglia‐enriched cultures. Using an antibody array and enzyme‐linked immunosorbent assay, we found that GSK‐3‐inhibitor treatment blocked LPS‐induced upregulation of regulated on activation normal T‐cell expressed and secreted (RANTES) and increased IL‐10 expression. The time kinetics and dose–response relations were confirmed. Reverse transcription–polymerase chain reaction showed changes on the messenger RNA level as well. Inhibiting GSK‐3 using short‐interference RNA, and transfecting cells with dominant‐negative GSK‐3β, blocked LPS‐elicited NO and RANTES expression but increased IL‐10 expression. In contrast, GSK‐3β overexpression upregulated NO and RANTES but downregulated IL‐10 in LPS‐stimulated cells. Treating cells with anti‐IL‐10 neutralizing antibodies to prevent GSK‐3 from downregulating NO and RANTES showed that the anti‐inflammatory effects are, at least in part, IL‐10‐dependent. The involvement of Akt, extracellular signal‐regulated kinase, p38 mitogen‐activated protein kinase and nuclear factor‐κB that positively regulated IL‐10 was demonstrated. Furthermore, inhibiting GSK‐3 increased the nuclear translocation of transcription factors, that all important for IL‐10 expression, including CCAAT/enhancer‐binding protein beat (C/EBPβ), C/EBPδ, cAMP response binding element protein and NF‐κB. Taken together, these findings reveal that LPS induces iNOS/NO biosynthesis and RANTES production through a mechanism involving GSK‐3‐mediated IL‐10 downregulation.