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Regulation of DNA damage responses by the Myc oncogene: implications for future anti-cancer therapies
Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). (Jonas Nilsson)
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Myc is a transcription factor frequently found deregulated in human cancer. Cells with deregulated expression of Myc carry a selective advantage against its neighbours due to the fact that Myc-mediated transcription governs crucial cellular events such as proliferation and growth. In addition, Myc has been implicated in several other aspects of tumour biology like cellular immortality, the formation of new blood vessels and the colonization of distant tissues through the process of metastasis. Therapy aimed at disrupting essential pathways regulated by Myc is important because of the many different types of cancers that depend on continued signalling along these pathways.  This thesis describes new treatment opportunities for cancers with a high Myc signature. In Paper Ι, we describe a new role for the DNA methyltransferase inhibitor Decitabine in the treatment of Myc transformed tumours cells. We show that the therapeutic potential of Decitabine in the treatment of Burkitt Lymphoma relies not only on its ability to cause reactivation of silenced genes such as pro-apoptotic PUMA, but also on the DNA damage that this drug induces. In vivo, Decitabine delays disease progression of transplanted lymphoma cells. In Paper ΙΙ, we identify the DNA damage checkpoint kinase Chk1 as a therapeutic target in Myc overexpressing cancers. We show that targeting Chk1 with shRNA or with a novel small molecule inhibitor cause a delay in disease progression of transplanted lymphoma cells in vivo. In Paper ΙΙΙ, the Chk1-related kinase Chk2 is evaluated as a therapeutic target in Myc overexpressing cancers. Myc overexpressing cells are not dependent on Chk2 but we show that Chk2 abrogation using shRNA causes polyploidization and protection against DNA damage. However, Chk2-targeted therapy elicits a synergistic lethal response in combination with inhibition of the DNA repair associated protein PARP. In conclusion, this thesis shows the potential of targeting the DNA damage machinery and the functional hubs important for maintenance of genomic stability in tumours with a deregulated expression of Myc.

Place, publisher, year, edition, pages
Umeå: Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet), Umeå universitet , 2011. , 96 p.
Keyword [en]
Myc, DNA damage, Decitabine, Chk1, Chk2
National Category
Biochemistry and Molecular Biology
Research subject
Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-44284ISBN: 978-91-7459-231-3OAI: oai:DiVA.org:umu-44284DiVA: diva2:419923
Public defence
2011-09-09, Norrlands universitetssjukhus, våning 9,sal 933, Norrlands universitetssjukhus, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2011-05-30 Created: 2011-05-30 Last updated: 2011-05-30Bibliographically approved
List of papers
1. Myc sensitizes p53-deficient cancer cells to the DNA-damaging effects of the DNA methyltransferase inhibitor decitabine
Open this publication in new window or tab >>Myc sensitizes p53-deficient cancer cells to the DNA-damaging effects of the DNA methyltransferase inhibitor decitabine
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2009 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 113, no 18, 4281-4288 p.Article in journal (Refereed) Published
Abstract [en]

Decitabine (also referred to as 5-aza-2'-deoxycytidine) is a drug that has recently been approved by the Food and Drug Administration (FDA) for the treatment of myelodysplastic syndrome (MDS). The mechanism of action is believed to be the blocking of DNA methylation and thereby reactivating silenced genes involved in harnessing MDS. When analyzing reactivation of genes involved in Burkitt lymphoma (BL), we discovered that decitabine also sensitizes tumor cells by inducing DNA damage. This sensitization is grossly augmented by the MYC oncogene, which is overexpressed in BL, and occurs in cells lacking a functional p53 tumor suppressor pathway. In p53-deficient BL cells and p53(-/-) mouse embryo fibroblasts, Myc overrides a transient G2-block exerted by decitabine via activation of Chk1. This triggers aneuploidy and cell death that correlates with, but can occur in the absence of, Epstein-Barr virus (EBV) reactivation, caspase activation, and/or expression of the BH3-only protein Puma. In vivo modeling of Myc-induced lymphoma suggests that decitabine constitutes a potential new drug against lymphoma that would selectively sensitize tumor cells but spare normal tissue.

Place, publisher, year, edition, pages
The American Society of Hematology, 2009
Keyword
Myc
National Category
Cell and Molecular Biology
Research subject
Molecular Biology
Identifiers
urn:nbn:se:umu:diva-44268 (URN)10.1182/blood-2008-10-183475 (DOI)
Available from: 2011-05-30 Created: 2011-05-30 Last updated: 2011-09-06Bibliographically approved
2. Therapeutic implications for the induced levels of Chk1 in Myc- expressing cancer cells
Open this publication in new window or tab >>Therapeutic implications for the induced levels of Chk1 in Myc- expressing cancer cells
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2011 (English)In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 17, no 22, 7067-7079 p.Article in journal (Refereed) Published
Abstract [en]

Purpose: The transcription factor c-Myc (or "Myc") is a master regulator of pathways driving cell growth and proliferation. MYC is deregulated in many human cancers, making its downstream target genes attractive candidates for drug development. We report the unexpected finding that B-cell lymphomas from mice and patients exhibit a striking correlation between high levels of Myc and checkpoint kinase 1 (Chk1). Experimental Design: By in vitro cell biology studies as well as preclinical studies using a genetically engineered mouse model, we evaluated the role of Chk1 in Myc-overexpressing cells. Results: We show that Myc indirectly induces Chek1 transcript and protein expression, independently of DNA damage response proteins such as ATM and p53. Importantly, we show that inhibition of Chk1, by either RNA interference or a novel highly selective small molecule inhibitor, results in caspase-dependent apoptosis that affects Myc-overexpressing cells in both in vitro and in vivo mouse models of B-cell lymphoma. Conclusion: Our data suggest that Chk1 inhibitors should be further evaluated as potential drugs against Myc-driven malignancies such as certain B-cell lymphoma/leukemia, neuroblastoma, and some breast and lung cancers. Clin Cancer Res; 17(22); 7067-79. (C) 2011 AACR.

Place, publisher, year, edition, pages
Philadelphia: Association for Cancer Research, 2011
Keyword
Myc, Chk1
National Category
Biochemistry and Molecular Biology
Research subject
Molecular Biology
Identifiers
urn:nbn:se:umu:diva-44269 (URN)10.1158/1078-0432.CCR-11-1198 (DOI)000297158500014 ()
Available from: 2011-05-30 Created: 2011-05-30 Last updated: 2011-12-13Bibliographically approved
3. Chk2 deficiency in Myc overexpressing lymphoma cells elicits a synergistic lethal response in combination with PARP inhibition.
Open this publication in new window or tab >>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
Abstract [en]

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
Keyword
lymphoma, Myc, Chk1, Chk2, PARP, DNA damage, AZD-7762, ABT-888
National Category
Biochemistry and Molecular Biology Cell Biology
Research subject
Molecular Biology
Identifiers
urn:nbn:se:umu:diva-44270 (URN)10.4161/cc.10.20.17887 (DOI)000296570700037 ()22030621 (PubMedID)
Available from: 2011-05-30 Created: 2011-05-30 Last updated: 2013-03-13Bibliographically approved

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