Chk2 deficiency in Myc overexpressing lymphoma cells elicits a synergistic lethal response in combination with PARP inhibition.
2011 (English)In: Cell Cycle, ISSN 1538-4101, E-ISSN 1551-4005, Vol. 10, no 20, 3598-3607 p.Article in journal (Refereed) Published
Myc is a transcription factor frequently found deregulated in human cancer. The Myc- mediated cellular transformation process is associated with fast proliferative cells and inherent genomic instability, giving rise to malignant, invasive neoplasms with poor prognosis for survival. Transcription-independent functions of Myc include stimulation of replication. Excessive Myc expression stimulates a replication-associated DNA damage response that signal via the phosphoinositide 3-kinase (PI3K) related protein kinases (PIKKs) ATM and ATR. These in turn activate the DNA damage transducers Chk1 and Chk2. Here, we show that Myc can stimulate Chek2 transcript indirectly in vitro, as well as in B cells of !-Myc transgenic mice or in the intestine of ApcMin mice. However, Chk2 is dispensable for Myc’s ability to transform cells in vitro and for the survival of established lymphoma cells from !-Myc transgenic mice. Chk2 deficiency induces polyploidy and slow growth but the cells are viable and protected against DNA damage. However, inhibition of both Chk1/Chk2 with AZD7762 induces cell death and significantly delays disease progression of transplanted lymphoma cells in vivo. DNA damage recruits PARP family members to sites of DNA breaks that in turn facilitate the induction of DNA repair. Strikingly, combining Chk2 and PARP inhibition elicits a synergistic lethal response in the context of Myc overexpression. Our data indicates that only certain types of chemotherapy would give rise to a synergistic lethal response in combination with specific Chk2 inhibitors, which will be important if Chk2 inhibitors enter the clinic.
Place, publisher, year, edition, pages
Georgetown, TX: Landes Bioscience , 2011. Vol. 10, no 20, 3598-3607 p.
lymphoma, Myc, Chk1, Chk2, PARP, DNA damage, AZD-7762, ABT-888
Biochemistry and Molecular Biology Cell Biology
Research subject Molecular Biology
IdentifiersURN: urn:nbn:se:umu:diva-44270DOI: 10.4161/cc.10.20.17887ISI: 000296570700037PubMedID: 22030621OAI: oai:DiVA.org:umu-44270DiVA: diva2:419843