Annexin A2 is a novel Cellular Redox Regulatory Protein involved in Tumorigenesis

Abstract

Annexins are a structurally related family of calcium and phospholipid-binding proteins that are involved in the regulation of a wide range of molecular and cellular processes. Annexin A2 is unique among the annexins in that it possesses redox sensitive cysteine(s). The ubiquitous and abundant expression of ANXA2 in cells and its reactivity with hydrogen peroxide led us to hypothesize that this protein could play a role in cellular redox regulation. Here we show that ANXA2 protein levels are induced by hydrogen peroxide. Furthermore, depletion of ANXA2 resulted in the elevation of cellular reactive oxygen species (ROS) upon oxidative stress, increased activation of the ROS-induced pro-apoptotic kinases, JNK, p38 and Akt and elevated sensitivity to ROS-mediated cellular damage/death. ANXA2-null mice showed significantly elevated protein oxidation in the liver and lung tissues compared to WT mice. ANXA2 depleted cancer cells showed enhanced cellular protein oxidationconcomitant with decreased tumor growth compared to control cancer cells andboth the oxidation of cellular proteins and tumor growth deficit werereversed by the antioxidant N-acetyl cysteine, indicating that ANXA2 plays akey role in the regulation of cellular redox during tumorigenesis. Ex-vivo human cancer studies showed that up-regulation of the reduced form of ANXA2 is associated with protection of the tumor proteins from oxidation. In summary, our results indicate that ANXA2 plays an important role incellular redox regulation by protecting cells from oxidative stress, aneffect that is particularly important during tumorigenesis.

CDK5RAP1 deficiency induces cell cycle arrest and apoptosis in human breast cancer cell line by the ROS/JNK signaling pathway

“…Although it has been reported to be a tumor growth promoter (29), there is compelling evidence that ROS production surmounts cellular antioxidant defenses, triggering apoptosis (13), and cancer cells are more sensitive to rapid increases in ROS levels than normal cells. ROS-mediated cytotoxicity has also been identified as an important mechanism in some anticancer agents (30).…”

Annexin Proteins: Novel Promising Targets for Anticancer Drug Development

“…Annexin A2 can also function as an antioxidant. Downregulation of annexin A2 leads tumor cells to apoptosis through pro-apoptotic p38MAPK/ JNK/Akt signaling pathways upon hydrogen peroxide exposure [37].…”

Structure–function analysis of apical membrane‐associated molecules of the tegument of schistosome parasites of humans: prospects for identification of novel targets for parasite control

“…Annexins may thus have distinct roles in enabling survival of parasites when they are within the hosts. Some annexins are speculated to be involved in redox reactions and the regulation of reactive oxygen molecules in plants (Hofmann et al, 2003) (Konopka-Postupolska et al, 2011 and in mammals (Tanaka et al, 2004;Madureira et al, 2011;Madureira and Waisman, 2013).…”

“…Annexins may thus have distinct roles in enabling survival of parasites when they are within the hosts. Some annexins are speculated to be involved in redox reactions and the regulation of reactive oxygen molecules in plants (Hofmann et al, 2003) (Konopka-Postupolska et al, 2011 and in mammals (Tanaka et al, 2004;Madureira et al, 2011;Madureira and Waisman, 2013).Localization of Sm-Anx-B22 by fluorescence and electron microscopy in different species of schistosomes (Tararam et al, 2010;de la Torre-Escudero et al, 2012;Leow et al, 2014) demonstrates that the molecule is strongly associated with the tegument and the plasma membrane structures of the apical regions of the tegument of adult parasites (Figure 2). The molecule is expressed in human-parasitic phases of the parasite life cycle, suggesting a major role in surface membrane dynamics during life in the human host.…”