Chk1 Targeting Reactivates PP2A Tumor Suppressor Activity in Cancer Cells

Khanna, Anchit; Kauko, Otto; Böckelman, Camilla; Laine, Antti; Schreck, Ilona; Partanen, Juhaní; Szwajda, Agnieszka; Bormann, Stefanie; Bilgen, Türker; Helenius, Merja; Pokharel, Yuba Raj; Pimanda, John E.; Russel, Mike R.; Haglund, Caj; Cole, Kristina A.; Klefström, Juha; Aittokallio, Tero; Weiss, Carsten; Ristimäki, Ari; Visakorpi, Tapio; Westermarck, Jukka

doi:10.1158/0008-5472.can-13-1002

Cited by 42 publications

(57 citation statements)

References 37 publications

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“…Although ETS1, ATF2, and E2F1 have been shown to directly bind to the CIP2A promoter, the MYCresponsive region within the CIP2A promoter has not yet been identified. More recently, we have identified DNA-damage kinase, CHK1, as a stimulator of CIP2A transcription in cancer cells in which CHK1 is constitutively phosphorylated on serine 345 by another DNA-damage kinase, DNA-PK (25). As DNA damage is present in most, if not all, cancer cells, these results may explain the widespread overexpression of CIP2A across multiple human cancer types.…”

Section: Cip2a Expression In Human Malignanciesmentioning

confidence: 90%

“…. In addition, small molecule inhibitors of the DNA-PK and CHK1 DNA damage signaling kinases inhibit CIP2A expression, and they induce PP2A activity in human cancer cells (25). Importantly, CIP2A downregulation was shown to be crucial for induction of the CHK1 inhibitor response, affecting cell survival in different cancer cell lines (25).…”

Section: Cip2a In Cancer Therapeuticsmentioning

confidence: 99%

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Cancerous Inhibitor of Protein Phosphatase 2A, an Emerging Human Oncoprotein and a Potential Cancer Therapy Target

2013

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Protein phosphatase 2A (PP2A) complexes function as tumor suppressors by inhibiting the activity of several critical oncogenic signaling pathways. Consequently, inhibition of the PP2A phosphatase activity is one of many prerequisites for the transformation of normal human cells into cancerous cells. However, mechanisms for PP2A inactivation in human cancers are poorly understood. The aberrant expression of cancerous inhibitor of protein phosphatase 2A (CIP2A), a recently identified endogenous PP2A inhibitor in malignant cells, is one such mechanism. Various independent studies have validated CIP2A's role in promoting tumor growth and resistance to apoptosis and senescence-inducing therapies. Notably, high CIP2A expression predicts poor patient prognosis in several human cancer types. Among the oncogenic proteins dephosphorylated by PP2A, the MYC oncoprotein, which is phosphorylated at serine 62, has surfaced as a marker for the oncogenic activity of CIP2A. The positivefeedback loop between CIP2A and MYC augments the activity of MYC in cancer cells. In addition, CIP2A promotes the phosphorylation and activity of additional oncoproteins, including E2F1 and AKT. However, CIP2A is not essential for normal mouse growth and development. These findings indicate that CIP2A is a novel anticancer target based on PP2A reactivation and inhibition of the oncogenic activity of its downstream effectors. The potential approaches and feasibility of targeting CIP2A are discussed here. Cancer Res; 73(22); 6548-53. Ó2013 AACR.

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Section: Cip2a Expression In Human Malignanciesmentioning

confidence: 90%

Section: Cip2a In Cancer Therapeuticsmentioning

confidence: 99%

Cancerous Inhibitor of Protein Phosphatase 2A, an Emerging Human Oncoprotein and a Potential Cancer Therapy Target

2013

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“…44), checkpoint kinase Chk1 could be the most promising candidate to be targeted for prosenescence therapy, as Chk1 inhibitors are already in clinical trials (55). We recently demonstrated that inhibition of constitutive Chk1 activity in various cancer cell lines reduces CIP2A expression resulting in PP2A reactivation and potent inhibition of malignant cell growth (67), whereas increased Chk1 expression was shown to protect against oncogene-induced replicative stress and to promote transformation (68). Finally, as different PP2A complexes mediate senescence induction and regulate E2F1 (49), testing of efficacy of small-molecule activators of PP2A (17,47) as novel prosenescence therapeutic agents might be warranted.…”

Section: Senescence Induction In Cancer Cells With Compromised P53 Fumentioning

confidence: 99%

Molecular Pathways: Harnessing E2F1 Regulation for Prosenescence Therapy in p53-Defective Cancer Cells

Laine

Westermarck

2014

Clinical Cancer Research

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Induction of terminal proliferation arrest, senescence, is important for in vivo tumor-suppressive function of p53. Moreover, p53-mutant cells are highly resistant to senescence induction by either oncogenic signaling during cellular transformation or in response to different therapies. Senescence resistance in p53-mutant cells has been attributed mostly to inhibition of the checkpoint function of p53 in response to senescence-inducing stress signals. Here, we review very recent evidence that offers an alternative explanation for senescence resistance in p53-defective cancer cells: p21-mediated E2F1 expression. We discuss the potential relevance of these findings for senescence-inducing therapies and highlight cyclin-dependent kinases (CDK) and mechanisms downstream of retinoblastoma protein (RB) as prospective prosenescence therapeutic targets. In particular, we discuss recent findings indicating an important role for the E2F1-CIP2A feedback loop in causing senescence resistance in p53-compromised cancer cells. We further propose that targeting of the E2F1-CIP2A feedback loop could provide a prosenescence therapeutic approach that is effective in both p53-deficient and RB-deficient cancer cells, which together constitute the great majority of all cancer cells. Diagnostic evaluation of the described senescence resistance mechanisms in human tumors might also be informative for patient stratification for already existing therapies. Clin Cancer Res; 20(14); 3644-50. Ó2014 AACR.

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“…An endogenous PP2A inhibitor protein, cancerous inhibitor of PP2A (CIP2A), promotes malignant cell proliferation, and tumor growth in various cancer models [13][14][15][16]. Overexpression of CIP2A associates with poor patient prognosis and tumor aggressiveness in virtually all cancer types studied thus far, including breast cancer, prostate cancer, and oral HNSCC [14][15]17,18].…”

Section: Potential Role For Cip2a and Stem Cell Marker Oct4 As Cancermentioning

confidence: 99%

“…Importantly, both Oct4-driven CIP2A expression in testicular cancer cells [21], and CIP2A expression in regenerating irradiated mouse intestines [27], promoted expression of oncogenic serine 62 phosphorylated form of MYC. Furthermore, CIP2A expression was shown to define cancer cell response to checkpoint kinase Chk1 inhibitors used in clinical cancer trials [16]. Moreover, high CIP2A expression predicts for poor patient survival of ovarian cancer patients after treatment with DNA damaging platinumbased agents [28], and to promote breast cancer cell resistance to doxorubicin [29].…”

Section: Introductionmentioning

confidence: 99%

CIP2A as a Potential Stratification Marker and Target for Tumor Responsiveness to DNA Damaging Therapies

Routila¹,

Westermarck²

2015

J Mol Biomark Diagn

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Head and neck squamous cell carcinoma; Radiation; Ovarian cancer; CHK1; Therapy response; Oct4; Cancer stem cell; CD24; CD44; MYC IntroductionDNA damaging therapies such as irradiation therapy and chemotherapy are used in the treatment of numerous cancer types both definitively and in combination with surgery. Cancer cells intrinsic resistance to DNA damaging therapies leads to failure in the successful eradication of cancer [1]. Mechanisms leading to DNA damage tolerance are inadequately known. It has been suggested, that there is a subpopulation of cancer cells, cancer stem cells, that would be responsible for the self-renewal potential of the tumor, and thus eventually, failed therapy response [2].Head and neck squamous cell carcinoma (HNSCC), the 6th most common cancer in the world, is treated with a combination of radiotherapy, radical surgery and platinum-based chemotherapeutics [3,4]. Recently, radiosensitization using EGFR inhibitors has challenged traditional chemotherapy [5]. While either radical surgery or definitive radiotherapy alone is often a sufficient treatment option for small local tumors, better loco regional control of more advanced disease is achieved with a combination of chemotherapeutics, surgery and irradiation [4]. Currently, there are no available biomarkers for the selection of suitable treatment modalities, which is thus solely based on patient characteristics and TNM staging of the cancer [6]. However, HNSCC has started to emerge as a set of cancers with very different behavioral patterns depending on tumor site, radiotolerance, carcinogen exposure, and stromal reaction [7][8][9]. These features and their clinical significance are as yet poorly characterized. Copious studies have lately aimed at identification of HNSCC subgroups for both prognostic and therapy stratification purposes [10]. Several potential biomarkers have been identified in HNSCC, but none of the studied biomarkers yet yield sufficient resolution to support their routine clinical use [6]. Promisingly, several clinical trials have recently been launched to study HPV infection as a predictive biomarker for reduced-intensity radiotherapy and EGFR inhibitor response in oropharyngeal HNSCC (ClinicalTrials.gov). The effect of HPV infection on prognosis of other HNSCC subclasses, however, is under debate [11]. Potential Role for CIP2A and Stem Cell Marker Oct4 as Cancer Patient Stratification Marker for DNA Damaging TherapiesUbiquitous protein phosphatase 2A (PP2A) complexes regulate serine/threonine phosphorylation of diverse cellular signaling pathways related to growth, cell viability, and malignant transformation [12]. An endogenous PP2A inhibitor protein, cancerous inhibitor of PP2A (CIP2A), promotes malignant cell proliferation, and tumor growth in various cancer models [13][14][15][16]. Overexpression of CIP2A associates with poor patient prognosis and tumor aggressiveness in virtually all cancer types studied thus far, including breast cancer, prostate cancer, and oral HNSCC [14][15]17,18]. In HNSCC particularly,...

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Chk1 Targeting Reactivates PP2A Tumor Suppressor Activity in Cancer Cells

Cited by 42 publications

References 37 publications

Cancerous Inhibitor of Protein Phosphatase 2A, an Emerging Human Oncoprotein and a Potential Cancer Therapy Target

Cancerous Inhibitor of Protein Phosphatase 2A, an Emerging Human Oncoprotein and a Potential Cancer Therapy Target

Molecular Pathways: Harnessing E2F1 Regulation for Prosenescence Therapy in p53-Defective Cancer Cells

CIP2A as a Potential Stratification Marker and Target for Tumor Responsiveness to DNA Damaging Therapies

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