Therapeutic Implications for the Induced Levels of Chk1 in Myc-Expressing Cancer Cells

Höglund, Andreas; Nilsson, Lisa M.; Muralidharan, Somsundar Veppil; Hasvold, Lisa; Merta, Philip J.; Rudelius, Martina; Nikolova, Viktoriya D.; Keller, Ulrich; Nilsson, Jonas A.

doi:10.1158/1078-0432.ccr-11-1198

Cited by 127 publications

(149 citation statements)

References 50 publications

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“…In this context, our data provide the first example of a tumor suppressor (Chk1) for which a supraphysiological dose facilitates transformation through diminishing oncogeneinduced stress. Interestingly, Chk1 expression is under the control of Myc and E2F onco genes, and increased Chk1 levels have been observed in lym phomas and breast carcinomas (Verlinden et al, 2007;Höglund et al, 2011). Moreover, public microarray repositories show that upregulation of Chk1, rather than downregulation, is a very frequent event in cancer (http://www.oncomine.org).…”

Section: Resultsmentioning

confidence: 99%

An extra allele of Chk1 limits oncogene-induced replicative stress and promotes transformation

López-Contreras¹,

Gutierrez-Martinez²,

Specks³

et al. 2012

J Cell Biol

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Replicative stress (RS) is a type of endogenous DNA damage that cells suffer every time they duplicate their genomes, and which is further boosted by oncogenes. In mammals, the RS response (RSR) is coordinated by ATR and Chk1 kinases. We sought to develop a mammalian organism that is selectively protected from RS. To this end, mice carrying an extra copy of the Chk1 gene were generated. In vitro, Chk1 transgenic cells are protected from RS-inducing agents. Moreover, an extra Chk1 allele prolongs the survival of ATR-Seckel mice, which suffer from high levels of RS, but not that of ATM-deficient mice, which accumulate DNA breaks. Surprisingly, increased Chk1 levels favor transformation, which we show is associated with a reduction in the levels of RS induced by oncogenes. Our study provides the first example where supra-physiological levels of a tumor suppressor can promote malignant transformation, which is a result of the protection from the RS found in cancer cells.

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Section: Resultsmentioning

confidence: 99%

An extra allele of Chk1 limits oncogene-induced replicative stress and promotes transformation

López-Contreras¹,

Gutierrez-Martinez²,

Specks³

et al. 2012

J Cell Biol

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“…Checkpoints in G 2 protect tumor cells with damaged DNA and replication stress entering premature and lethal mitosis resulting in apoptosis or mitotic catastrophe [8]. However, activation of Chk1 in tumor cells can also facilitate checkpoint override and illegitimate cell-cycle progresssion resulting in tumor progression with increased genomic instability [34].…”

Section: Discussionmentioning

confidence: 99%

Gemcitabine Inhibits Murine Head and Neck Squamous Cell Carcinoma Growth via Proteasome-Dependent Degradation of Chk1 Leading to Cell Cycle Arrest and Apoptosis

Song¹,

Wu²,

Whitaker³

et al. 2012

JCT

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Head and neck squamous cell carcinoma (HNSCC) is a common tumor worldwide that often presents at an advanced stage with poor prognosis. Advanced HNSCC frequently exhibits resistance to chemotherapy limiting its efficacy. Gemcitabine is a pyrimidine-based analog that is currently used for the treatment of metastatic pancreatic cancer. In this study, we examined the anti-tumor effects of gemcitabine in a highly aggressive murine model of HNSCC (LY2). In vitro cell viability and in vivo tumor growth inhibitory assays were carried out to determine the sensitivity of LY2 cells to gemcitabine. Immunohistochemical, Western blotting, RT-PCR and RNAi-mediated silencing assays were used to characterize effects of gemcitabine cell proliferation, DNA synthesis, apoptosis, pro-survival and DNA damage response signaling pathways. LY2 cells treated with gemcitabine undergo apoptosis mediated by the activation of both caspase-3 and -9. Gemcitabine on treatment induces rapid phosphorylation of checkpoint kinase 1 (Chk1) in LY2 cells and subsequent degradation in a time and dose dependent manner. Proteasome inhibitor MG132 blocks Chk1 degradation and decreases LY2 cells susceptibility to gemcitabine. Inhibition of Chk1 function, either using inhibitor PD 407824 or small interfering RNA (siRNA), increases the sensitivity of LY2 cells to gemcitabine. Gemcitabine treatment resulted in significant reduction in tumor growth relative to saline-treated control in a syngeneic orthotopic murine model of HNSCC. Gemcitabine-induced DNA replication stress in LY2 cells activates Chk1 by phosphorylation and promotes Chk1 degradation via the ubiquitin-proteasome pathway. Depletion of Chk1 terminates S-phase check point in LY2 cells resulting in apoptotic cell death. Our data provides an important rationale for integrating gemcitabine to optimize chemotherapeutic efficacy in HNSCC.

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“…On the contrary, ATR and Chk1 expression are frequently upregulated in cancer, in part because they are cell-cycle regulated genes and tumours have high proliferative indexes. Moreover, the expression of Chk1 is under the control of oncogenes such as Myc or E2F [76,77], which might be responsible for its enhanced levels in certain tumours. Why would tumours select for higher ATR and Chk1 levels?…”

Section: Rs As a Brake For Tumorigenesismentioning

confidence: 99%

“…While most data with ATR inhibitors so far relates to in vitro studies due to the limited availability of ATR inhibitors that can work in vivo, some of the observations from ATR mutant mouse models could be validated with Chk1 inhibitors. First, Chk1 inhibitors showed efficacy on the treatment of Myc-lymphoma xenografts [10,76]. In addition, high levels of Chk1 are induced by N-Myc in a xenograft model of neuroblastoma, making the tumours highly sensitive to the treatment with Chk1 inhibitors [92,93].…”

Section: Targeting Rs In Cancer Treatmentmentioning

confidence: 99%

Replication stress and cancer: It takes two to tango

Lecona

Fernández-Capetillo

2014

Experimental Cell Research

119

107

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Problems arising during DNA replication require the activation of the ATR-CHK1 pathway to ensure the stabilization and repair of the forks, and to prevent the entry into mitosis with unreplicated genomes. Whereas the pathway is essential at the cellular level, limiting its activity is particularly detrimental for some cancer cells. Here we review the links between replication stress (RS) and cancer, which provide a rationale for the use of ATR and Chk1 inhibitors in chemotherapy. First, we describe how the activation of oncogene-induced RS promotes genome rearrangements and chromosome instability, both of which could potentially fuel carcinogenesis. Next, we review the various pathways that contribute to the suppression of RS, and how mutations in these components lead to increased cancer incidence and/or accelerated ageing. Finally, we summarize the evidence showing that tumours with high levels of RS are dependent on a proficient RS-response, and therefore vulnerable to ATR or Chk1 inhibitors.

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Therapeutic Implications for the Induced Levels of Chk1 in Myc-Expressing Cancer Cells

Cited by 127 publications

References 50 publications

An extra allele of Chk1 limits oncogene-induced replicative stress and promotes transformation

An extra allele of Chk1 limits oncogene-induced replicative stress and promotes transformation

Gemcitabine Inhibits Murine Head and Neck Squamous Cell Carcinoma Growth via Proteasome-Dependent Degradation of Chk1 Leading to Cell Cycle Arrest and Apoptosis

Replication stress and cancer: It takes two to tango

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