A signaling pathway consisting of miR-551b, catalase and MUC1 contributes to acquired apoptosis resistance and chemoresistance

Abstract

Acquired chemoresistance is a major challenge in cancer therapy. While the oncoprotein Mucin-1 (MUC1) performs multiple roles in the development of diverse human tumors, whether MUC1 is involved in acquired chemoresistance has not been determined. Using an acquired chemoresistance lung cancer cell model, we show that MUC1 expression was substantially increased in cells with acquired apoptosis resistance (AR). Knockdown of MUC1 expression effectively increased the sensitivity of these cells to the apoptotic cytotoxicity of anticancer therapeutics, suggesting that MUC1 contributes to acquired chemoresistance. Decreased catalase expression and increased cellular reactive oxygen species (ROS) accumulation were found to be associated with MUC1 overexpression. Scavenging ROS with butylated hydroxyanisole or supplying exogenous catalase dramatically suppressed MUC1 expression through destabilizing MUC1 protein, suggesting that reduced catalase expression mediated ROS accumulation is accounted for MUC1 overexpression. Further, we found that increased miR-551b expression in the AR cells inhibited the expression of catalase and potentiated ROS accumulation and MUC1 expression. Finally, by manipulating MUC1 expression, we found that MUC1 promotes EGFR-mediated activation of the cell survival cascade involving Akt/c-FLIP/COX-2 in order to protect cancer cells from responding to anticancer agents. Thus, our results establish a pathway consisting of miR-551b/catalase/ ROS that results in MUC1 overexpression, and intervention against this pathway could be exploited to overcome acquired chemoresistance.

Acute Hepatitis C Virus Infection Induces Consistent Changes in Circulating MicroRNAs That Are Associated with Nonlytic Hepatocyte Release

“…To date, only two other publications exist regarding the role of miR-551b in any biological process (52,53). Fu et al described a downregulation of miR-551b in hepatoma cells expressing a mutant of the hepatitis B virus HBx protein that induces higher levels of cellular proliferation, and Xu et al described a role for miR551b in acquired apoptosis and chemotherapy resistance in human lung cancer cell lines.…”

Role of the Unfolded Protein Response in Regulating the Mucin-Dependent Filamentous-Growth Mitogen-Activated Protein Kinase Pathway

“…Signaling mucins are composed of a highly glycosylated extracellular domain that contains a mucin homology domain (MHD), which is defined by tandem repeats rich in Ser/Thr/Pro residues. The extracellular domain is connected by a single-pass transmembrane (TM) alpha helix to a cytosolic signaling domain, which associates with a diverse array of proteins that regulate mitogen-activated protein kinase (MAPK) pathways, Akt, ␤-catenin, and other pathways (5)(6)(7)(8). Signaling mucins are overexpressed in different cancers, where they contribute to cell proliferation and metastasis (6).…”

Mucin 1 promotes radioresistance in hepatocellular carcinoma cells through activation of JAK2/STAT3 signaling

“…MUC1 has demonstrated the ability to modulate the apoptotic response in different cellular contexts. For instance, inhibition of MUC1 significantly induced apoptosis in pancreatic cancer cells (23) and increased the sensitivity of lung cancer cells to anticancer drug-induced apoptosis (24). Upregulation of MUC1 has been identified to render human bronchial epithelial cells more resistant to apoptosis following exposure to nickel acetate (25).…”