Inhibition of Mcl-1 Promotes Senescence in Cancer Cells: Implications for Preventing Tumor Growth and Chemotherapy Resistance

Overview

Journal Mol Cell Biol

Specialty Cell Biology

Date 2012 Mar 28

PMID 22451485

Citations 27

Authors

Elzbieta Bolesta

Lukas W Pfannenstiel

Abeba Demelash

Mathew L Lesniewski

Megan Tobin

Simon E Schlanger

Shreeram C Nallar

John C Papadimitriou

Dhan V Kalvakolanu

Brian R Gastman

Affiliations

Soon will be listed here.

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.

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