Oncotarget

Research Papers:

Regulation of the antiapoptotic protein cFLIP by the glucocorticoid Dexamethasone in ALL cells

Lara Kleinesudeik, Katharina Rohde and Simone Fulda _

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Oncotarget. 2018; 9:16521-16532. https://doi.org/10.18632/oncotarget.24782

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Abstract

Lara Kleinesudeik1,2,3, Katharina Rohde1 and Simone Fulda1,2,3

1Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Frankfurt, Germany

2German Cancer Consortium (DKTK), Partner site Frankfurt, Germany

3German Cancer Research Center (DKFZ), Heidelberg, Germany

Correspondence to:

Simone Fulda, email: simone.fulda@kgu.de

Keywords: apoptosis; cFLIP; glucocorticoid; Smac mimetic

Received: December 13, 2017     Accepted: February 26, 2018     Published: March 27, 2018

ABSTRACT

We recently reported that the Smac mimetic BV6 and glucocorticoids, e.g. Dexamethasone (Dexa), synergize to induce cell death in acute lymphoblastic leukemia (ALL) in vitro and in vivo. Here, we discover that this synergism involves Dexa-stimulated downregulation of cellular FLICE-like inhibitory protein (cFLIP) in ALL cells. Dexa rapidly decreases cFLIPL protein levels, which is further enhanced by addition of BV6. While attenuating the activation of non-canonical nuclear factor-kappaB (NF-κB) signaling by BV6, Dexa suppresses cFLIPL protein but not mRNA levels pointing to a transcription-independent downregulation of cFLIPL by Dexa. Analysis of protein degradation pathways indicates that Dexa causes cFLIPL depletion independently of proteasomal, lysosomal or caspase pathways, as inhibitors of the proteasome, lysosomal enzymes or caspases all failed to protect from Dexa-mediated loss of cFLIPL protein. Also, Dexa alone or in combination with BV6 does not affect overall activity of the proteasome. Importantly, overexpression of cFLIPL to an extent that is no longer subject to Dexa-imposed downregulation rescues Dexa/BV6-mediated cell death. Vice versa, knockdown of cFLIP increases BV6-mediated cell death, thus mimicking the effect of Dexa. Altogether, these data demonstrate that Dexa-mediated downregulation of cFLIPL protein promotes Dexa/BV6-mediated cell death, thereby providing novel insights into the synergistic antitumor activity of this combination treatment.


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