Abstract
The recently discovered CHK1-Suppressed (CS) pathway is activated by inhibition or loss of the checkpoint kinase CHK1, promoting an apoptotic response to DNA damage mediated by caspase-2 in p53-deficient cells. Although functions of the CS-pathway have been investigated biochemically, it remains unclear whether and how CHK1 inhibition can be regulated endogenously and whether this constitutes a key component of the DNA damage response (DDR). Here, we present data that define the first endogenous activation of the CS-pathway whereby, upon DNA damage, wild type p53 acts as an endogenous regulator of CHK1 levels that modulates caspase-2 activation. Moreover, we demonstrate that persistence of CHK1 levels in response to DNA damage in p53-deficient cancer cells, leads to CHK1-mediated activation of NF-κB and induction of NF-κB-regulated genes in cells and in associated tumor-derived microvesicles (TMVs), both of which are abrogated by loss or inhibition of CHK1. These data define a novel role for CHK1 in the DDR pathway as a regulator NF-κB activity. Our data provide evidence that targeting CHK1 in p53-deficient cancers may abrogate NF-κB signaling that is associated with increased cellular survival and chemoresistance.
Highlights
Alterations in p53 are amongst the most frequent in all human cancers and are associated with increased capacity to evade apoptosis leading to therapeutic resistance; elucidating p53-independent DNA damage response (DDR) pathways that could overcome this resistance has been an intense area of research [1,2,3,4]
The functions of the CS-pathway have been probed through pharmacological inhibition and siRNA knockdown [4, 5], it is unclear whether and how CHK1 inhibition can be regulated endogenously
Levels of p53 and CHK1 were assessed as well as caspase-2 processing in response to doxorubicin in MCF7 breast cancer cells that are wild type (WT) for p53
Summary
Alterations in p53 are amongst the most frequent in all human cancers and are associated with increased capacity to evade apoptosis leading to therapeutic resistance; elucidating p53-independent DDR pathways that could overcome this resistance has been an intense area of research [1,2,3,4]. During the CS-pathway, loss or inhibition of CHK1 in the context of mutant p53 circumvents p53 status to promote a caspase-2 apoptotic response to DNA damage [4, 5]. Caspase-2 is a poorly defined but evolutionarily conserved member of the caspase family. It is activated by proximity-induced oligomerization via recruitment to a high molecular weight platform termed the PIDDosome. In addition to activating caspase-2, PIDD can activate NF-κB in response to DNA damage forming a separate PIDDosome complex that lacks RAIDD and caspase-2 but contains RIPK1 and NEMO (NF-κB essential modulator)/IKKγ [8]. Unlike caspase-2, NF-κB is a transcription factor whose activity results in induction of pro-survival genes in addition to a number of chemokines and cytokines [9]; PIDD can elicit either pro-survival or pro-death signals according to its protein interactions [10]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
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.
