PTH1–34 Blocks Radiation-induced Osteoblast Apoptosis by Enhancing DNA Repair through Canonical Wnt Pathway

Chandra, Abhishek; Lin, Tiantian; Zhu, Jing; Tong, Wei; Huo, Yanying; Jia, Huixian; Zhang, Yejia; Liu, X. Sherry; Cengel, Keith A.; Xia, Bing; Qin, Ling

doi:10.1074/jbc.m114.608158

Cited by 55 publications

(53 citation statements)

References 53 publications

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“…Our study builds on previous work implicating β-catenin in the regulation of genome stability (Aoki et al, 2007;Dose et al, 2014) and in the DNA damage response (Chandra et al, 2015;Priolli et al, 2013;Tavana et al, 2013;Xu et al, 2008;Zhang et al, 2011). Indeed, our data align well with these previous reports.…”

Section: Discussionsupporting

confidence: 90%

“…This is in agreement with numerous studies showing that gain-of-function mutations in β-catenin signaling and loss of α-catenin regulation are prevalent in cancer (Aaltomaa et al, 1999;Anttila et al, 1998;Clevers and Nusse, 2012;Gofuku et al, 1999;Lifschitz-Mercer et al, 2001;Matsui et al, 1994;Nakopoulou et al, 2002;Polakis, 2000;Richmond et al, 1997;Rimm et al, 1995;Shiozaki et al, 1994;Silvis et al, 2011;Tanaka et al, 2003;van Oort et al, 2007;Yang et al, 2006). This additional level of regulation by α-catenin may help explain why WNT stimulation has been reported to decrease the sensitivity of cells to DNA damage despite increased nuclear β-catenin levels (Chandra et al, 2015;Chen et al, 2007;Jun et al, 2016;Woodward et al, 2007), and why different experimental systems have had confounding results (Chevillard-Briet et al, 2014;Orford et al, 1999;Tao et al, 2015;Watson et al, 2010). Intriguingly, p53 is able to regulate WNT ligand production in a cell type-dependent manner (Lee et al, 2010) as well as β-catenin levels (Kim et al, 2011; Sadot Our results suggest that the effect of WNT stimulation on the DNA damage response may depend on the levels of nuclear α-catenin, as well as those of β-catenin and other proteins recruited to this complex.…”

Section: Discussionmentioning

confidence: 98%

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Nuclear α-catenin mediates the DNA damage response via β-catenin and nuclear actin

Serebryannyy

Yemelyanov

Gottardi

et al. 2017

Journal of Cell Science

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α-Catenin is an F-actin-binding protein widely recognized for its role in cell-cell adhesion. However, a growing body of literature indicates that α-catenin is also a nuclear protein. In this study, we show that α-catenin is able to modulate the sensitivity of cells to DNA damage and toxicity. Furthermore, nuclear α-catenin is actively recruited to sites of DNA damage. This recruitment occurs in a β-catenindependent manner and requires nuclear actin polymerization. These findings provide mechanistic insight into the WNT-mediated regulation of the DNA damage response and suggest a novel role for the α-catenin-β-catenin complex in the nucleus.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 98%

Nuclear α-catenin mediates the DNA damage response via β-catenin and nuclear actin

Serebryannyy

Yemelyanov

Gottardi

et al. 2017

Journal of Cell Science

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“…Zhao and colleagues observed that an upregulation of the Wnt/β-catenin pathway accelerates mucosal repair following radiotherapy-induced oral mucositis (33). Very recently, Chandra and colleagues demonstrated that an activated Wnt/β-catenin pathway blocks radiation-induced apoptosis in osteoblasts through enhanced DNA repair, suggesting that Wnt agonists may be clinically used to block radiation-induced osteoporosis (34). In a similar attempt, we stimulated phenotypically “normal” RPE-1 cells, which are highly sensitive to irradiation, with Wnt-3a, a physiological ligand of the Frizzled receptor family.…”

Section: Discussionmentioning

confidence: 99%

Chemoradiotherapy Resistance in Colorectal Cancer Cells is Mediated by Wnt/β-catenin Signaling

Emons

Spitzner

Reineke

et al. 2017

Molecular Cancer Research

114

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Activation of Wnt/β-catenin signaling plays a central role in the development and progression of colorectal cancer (CRC). The Wnt-transcription factor, TCF7L2, is overexpressed in primary rectal cancers that are resistant to chemoradiotherapy (CRT) and TCF7L2 mediates resistance to CRT. However, it is unclear whether the resistance is mediated by a TCF7L2 inherent mechanism or Wnt/β-catenin signaling in general. Here, inhibition of β-catenin by siRNAs or a small molecule inhibitor (XAV-939) resulted in sensitization of CRC cells to CRT. To investigate the potential role of Wnt/β-catenin signaling in controlling therapeutic responsiveness, non-tumorigenic RPE-1 cells were stimulated with Wnt-3a, a physiological ligand of Frizzled-receptors, which increased resistance to CRT. This effect could be recapitulated by overexpression of a degradation-resistant mutant of β-catenin (S33Y), also boosting resistance of RPE-1 cells to CRT, which was, conversely, abrogated by siRNA-mediated silencing of β-catenin. Consistent with these findings, higher expression levels of active β-catenin were observed as well as increased TCF/LEF reporter activity in SW1463 cells that evolved radiation resistance due to repeated radiation treatment. Global gene expression profiling identified several altered pathways, including PPAR signaling and other metabolic pathways, associated with cellular response to radiation. In summary, aberrant activation of Wnt/β-catenin signaling not only regulates the development and progression of colorectal cancer, but also mediates resistance of rectal cancers to chemoradiotherapy. Implications Targeting Wnt/β-catenin signaling or one of the downstream pathways represents a promising strategy to increase response to CRT.

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“…In this study, an increase was seen in D q in β-catenin overexpressed CNE-2 cells, as revealed by the cell survival curve, indicating the enhanced ability in the repair of sublethal cellular damages, and this may be associated with the overexpression of β-catenin. It was found that activation of the β-catenin pathway effectively promoted the repair of DNA double strand breaks (DSBs) in irradiated osteoblasts [41], and up-regulation of β-catenin expression increased the capacity of DSB repair in cancer cells [42].It is therefore considered that the role of β-catenin in DNA damage repair may be a factor affecting cellular radiation sensitivity.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of β-Catenin Decreases the Radiosensitivity of Human Nasopharyngeal Carcinoma CNE-2 Cells

Kang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Nasopharyngeal carcinoma (NPC) is rare worldwide but remains highly prevalent in endemic regions, notably in southern China. Radiotherapy remains the treatment of choice for NPC, but radioresistance has been identified as a major cause of therapeutic failure. The Wnt/β-catenin signaling has been found to be involved in NPC radioresistance; however, the effect of β-catenin overexpression on radioresistance remains unknown in NPC until now. This study aimed to examine the impact of β-catenin overexpression on the radiosensitivity of human NPC CNE-2 cells. Methods: Immunohistochemistry was performed to detect the β-catenin expression in normal nasopharyngeal specimens and NPC specimens. The human NPC CNE-2 cell line overexpressing β-catenin was modeled by transfection with the pcDNA3.1/Hygro(+)/β-catenin recombinant vector (transfection group), while cells transfected with the pcDNA3.1/Hygro(+) vector served as negative controls and non-transfected cells served as blank controls. The expression of key molecules of the Wnt/β-catenin signaling pathway was determined using Western blotting and qPCR assays, and the changes of radiation sensitivity were measured with a colony-formation assay. Cell viability was measured by the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5 -diphenyltetrazolium bromide) assay. In addition, the cell cycle and apoptosis was detected using flow cytometry and the TCF/LEF transcriptional activity was measured with a Dual Luciferase Reporter Assay System. Results: Immunohistochemical staining showed high β-catenin expression in radioresistant NPC specimens, and low expression in radiosensitive NPC specimens and normal nasopharyngeal specimens. Western blotting and qPCR assays detected higher β-catenin expression in the transfection group than in the negative and blank controls (P < 0.01). Down-regulation of GSK-3β expression (P < 0.05) and up-regulation of Cyclin D1 expression (P < 0.01) was detected in β-catenin overexpressing NPC cells exposed to X-ray radiation relative to negative and blank controls. Colony-formation assay revealed higher D₀, D_q and SF in the transfection group than in the negative and blank control groups post-radiation, and the SER in the transfection group was 0.75-fold and 0.68-fold greater than that in the blank and negative control groups, respectively. MTT assay revealed that the viability of CNE-2 cells was significantly higher in the transfection group (96% ± 8.72%) than in the negative control group (74.67 ± 7.05%) and the blank control group (75.33% ± 7.02%) 24 h post-exposure to 6 Gy X-ray radiation (P < 0.05). X-ray radiation led to a lower proportion of CNE-2 cells at the G2/M phase and a lower apoptotic rate in the transfection group than in the negative and blank control groups (P < 0.05). In addition, the TCF/LEF transcriptional activity was higher in the transfection group than in the negative and blank control groups (P < 0.01), and 6 Gy X-ray radiation elevated the TCF/LEF transcriptional activity relative to 0 Gy radiation ...

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PTH1–34 Blocks Radiation-induced Osteoblast Apoptosis by Enhancing DNA Repair through Canonical Wnt Pathway

Cited by 55 publications

References 53 publications

Nuclear α-catenin mediates the DNA damage response via β-catenin and nuclear actin

Nuclear α-catenin mediates the DNA damage response via β-catenin and nuclear actin

Chemoradiotherapy Resistance in Colorectal Cancer Cells is Mediated by Wnt/β-catenin Signaling

Overexpression of β-Catenin Decreases the Radiosensitivity of Human Nasopharyngeal Carcinoma CNE-2 Cells

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