title: 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.
authors.affiliation: Molecular Biology and Lung Cancer Program, Lovelace Respiratory Research Institute, 2425 Ridgecrest Drive, Albuquerque, NM 87108, USA and Department of Physiology & Lung Center, Temple University School of Medicine, 3420 North Broad Street, Philadelphia, PA 19140, USA.
authors.forename: Xiuling
authors.initials: X
authors.lastname: Xu
authors.affiliation: Molecular Biology and Lung Cancer Program, Lovelace Respiratory Research Institute, 2425 Ridgecrest Drive, Albuquerque, NM 87108, USA and Department of Physiology & Lung Center, Temple University School of Medicine, 3420 North Broad Street, Philadelphia, PA 19140, USA.
authors.forename: Alexandria
authors.initials: A
authors.lastname: Wells
authors.affiliation: Molecular Biology and Lung Cancer Program, Lovelace Respiratory Research Institute, 2425 Ridgecrest Drive, Albuquerque, NM 87108, USA and Department of Physiology & Lung Center, Temple University School of Medicine, 3420 North Broad Street, Philadelphia, PA 19140, USA.
authors.forename: Mabel T
authors.initials: MT
authors.lastname: Padilla
authors.affiliation: Department of Physiology & Lung Center, Temple University School of Medicine, 3420 North Broad Street, Philadelphia, PA 19140, USA.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Kato
authors.affiliation: Department of Physiology & Lung Center, Temple University School of Medicine, 3420 North Broad Street, Philadelphia, PA 19140, USA.
authors.forename: Kwang Chul
authors.initials: KC
authors.lastname: Kim
authors.affiliation: Molecular Biology and Lung Cancer Program, Lovelace Respiratory Research Institute, 2425 Ridgecrest Drive, Albuquerque, NM 87108, USA and Department of Physiology & Lung Center, Temple University School of Medicine, 3420 North Broad Street, Philadelphia, PA 19140, USA ylin@lrri.org.
authors.forename: Yong
authors.initials: Y
authors.lastname: Lin
mesh_terms: D017209:Apoptosis / Q000235:genetics*; D002374:Catalase / Q000235:genetics*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D066246:ErbB Receptors / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics*; D035683:MicroRNAs / Q000235:genetics*; D018396:Mucin-1 / Q000096:biosynthesis* / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics
chemical_list: C000595937:MIRN-551 microRNA, human; C060192:MUC1 protein, human; D035683:MicroRNAs; D018396:Mucin-1; D017382:Reactive Oxygen Species; D002374:Catalase; C512478:EGFR protein, human; D066246:ErbB Receptors
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