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.
Highlights
Apoptosis is one of the best characterized forms of programmed cell death and a crucial process in physiological and pathophysiological conditions [1]
Since our data point to a transcription-independent regulation of cFLIPL, we investigated whether Dexastimulated downregulation of cFLIPL is due to changes in cellular protein degradation pathways. cFLIPL is described as short-lived protein, which is primarily regulated by the ubiquitin-proteasomal pathway [18]
We discover that Dexa-imposed suppression of cFLIPL contributes to Dexa/BV6-induced cell death
Summary
Apoptosis is one of the best characterized forms of programmed cell death and a crucial process in physiological and pathophysiological conditions [1]. Evasion of programmed cell death is a hallmark of cancer and accomplished, for example, by aberrant expression of antiapoptotic proteins. One major cell death regulator is cFLIP. High cFLIP expression is correlated with a poor prognosis in several tumor entities [4,5,6] and its downregulation is part of effective drug-mediated cell death [7]. There are two main isoforms of cFLIP expressed in human cells which control cell death in a distinct manner: The long isoform cFLIPL, a 55 kDa protein, and the short isoform cFLIPS, a 25 kDa protein [3]. Its influence on cell death regulation is being controversially discussed, as it is reported to exert pro- or antiapoptotic effects, depending on the context
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
