Essential role for Bim in mediating the apoptotic and antitumor activities of immunotoxins
Details
Publication Year 2017,Volume 36,Issue #35,Page 4953-4962
Journal Title
Oncogene
Publication Type
Journal Article
Abstract
Protein synthesis is crucial for regulating cell homeostasis and, when unrestricted, it can lead to tumorigenesis. Immunotoxins derived from Pseudomonas exotoxin are antibody-toxin fusion proteins that inhibit protein synthesis of mammalian cells via ADP-ribosylation of the eukaryotic elongation factor-2. Here we investigate the role of the Bcl-2 family proteins in the response of cancer cells to immunotoxin challenge. Besides the well-known reduction of the prosurvival Bcl-2 family member, Mcl-1, following inhibition of protein synthesis, we show for the first time that immunotoxins also reduce the levels of selected proapoptotic BH-3-only proteins. Among these, only Bim protein levels correlated with the ability of immunotoxins to induce an apoptotic response. To support our findings, we verified that a Bim knockout completely abolished immunotoxin-mediated apoptosis. Further, mice bearing either wild-type or Bid knockout tumors responded to immunotoxin treatment with a decrease in growth kinetics, whereas mice engrafted with Bim knockout tumors showed no reduction in tumor size or prolongation of survival following immunotoxin treatment. From these results, we conclude that Bim expression is a major susceptibility factor for tumor cell death and, as such, constitutes a potential biomarker that could be evaluated before immunotoxin treatment. In support of this hypothesis, clinically, we analyzed patient cells before immunotoxin treatment and report that samples of hairy cell leukemia with high levels of Bim protein responded with a greater decrease in leukemic cell count compared with those samples expressing a low level of Bim.Oncogene advance online publication, 24 April 2017; doi:10.1038/onc.2017.111.
Publisher
Springer Nature
Research Division(s)
Cancer And Haematology
PubMed ID
28436946
NHMRC Grants
NHMRC/1057742NHMRC/1016701
Terms of Use/Rights Notice
Refer to copyright notice on published article.


Creation Date: 2017-05-02 03:01:22
Last Modified: 2018-07-09 03:43:51
An error has occurred. This application may no longer respond until reloaded. Reload 🗙