title: Inhibition of Mcl-1 promotes senescence in cancer cells: implications for preventing tumor growth and chemotherapy resistance.
abstract: Although senescence in oncogenesis has been widely studied, little is known regarding the role of this process in chemotherapy resistance. Thus, from the standpoint of enhancing and improving cancer therapy, a better understanding of the molecular machinery involved in chemotherapy-related senescence is paramount. We show for the first time that Mcl-1, a Bcl-2 family member, plays an important role in preventing chemotherapy-induced senescence (CIS). Overexpression of Mcl-1 in p53⁺ cell lines inhibits CIS. Conversely, downregulation of Mcl-1 makes cells sensitive to CIS. Surprisingly, downregulation of Mcl-1 in p53⁻ cells restored CIS to similar levels as p53⁺ cells. In all cases where senescence can be induced, we observed increased p21 expression. Moreover, we show that the domain of Mcl-1 responsible for its antisenescent effects is distinct from that known to confer its antiapoptotic qualities. In vivo we observe that downregulation of Mcl-1 can almost retard tumor growth regardless of p53 status, while overexpression of Mcl-1 in p53⁺ cells conferred resistance to CIS and promoted tumor outgrowth. In summary, our data reveal that Mcl-1 can inhibit CIS in both a p53-dependent and -independent manner in vitro and in vivo and that this Mcl-1-mediated inhibition can enhance tumor growth in vivo.
authors.affiliation: Department of Surgery, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Bolesta
authors.forename: Lukas W
authors.initials: LW
authors.lastname: Pfannenstiel
authors.forename: Abeba
authors.initials: A
authors.lastname: Demelash
authors.forename: Mathew L
authors.initials: ML
authors.lastname: Lesniewski
authors.forename: Megan
authors.initials: M
authors.lastname: Tobin
authors.forename: Simon E
authors.initials: SE
authors.lastname: Schlanger
authors.forename: Shreeram C
authors.initials: SC
authors.lastname: Nallar
authors.forename: John C
authors.initials: JC
authors.lastname: Papadimitriou
authors.forename: Dhan V
authors.initials: DV
authors.lastname: Kalvakolanu
authors.forename: Brian R
authors.initials: BR
authors.lastname: Gastman
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*
chemical_list: C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2