Jaridonin-induced G2/M phase arrest in human esophageal cancer cells is caused by reactive oxygen species-dependent Cdc2-tyr15 phosphorylation via ATM–Chk1/2–Cdc25C pathway

Ma, Yongcheng; Su, Nan; Shi, Xiaojing; Zhao, Wen; Yu, Ke; Zi, Xiaolin; Zhao, Na; Qin, Yuhua; Zhao, Hongwei; Liu, Hong‐Min

doi:10.1016/j.taap.2014.11.003

Cited by 38 publications

(20 citation statements)

References 31 publications

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“…Phosphorylation of Cdc2 is accomplished by two major regulators, Wee1 and Myt1, which phosphorylate Cdc2 at Tyr‐15 and Thr‐14, respectively . Cdc2 (Tyr‐15) is activated by Cdc25C, a dual‐specific phosphatase, whose activity is essential for entry into mitosis during drug‐induced G2/M arrest . The aberrant expression of DNA damage response genes (e.g., BRCA1 , BRIT1 and PARP‐1 ) is common in nearly all breast cancer phenotypes .…”

Section: Introductionmentioning

confidence: 99%

“…4 Cdc2 (Tyr-15) is activated by Cdc25C, a dual-specific phosphatase, whose activity is essential for entry into mitosis during drug-induced G2/M arrest. 5 The aberrant expression of DNA damage response genes (e.g., BRCA1, BRIT1 and PARP-1) is common in nearly all breast cancer phenotypes. 6 One of the major checkpoints in mammalian cells is mediated by checkpoint kinase 1 (CHK1).…”

Section: Introductionmentioning

confidence: 99%

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DNA primase polypeptide 1 (PRIM1) involves in estrogen‐induced breast cancer formation through activation of the G2/M cell cycle checkpoint

Lee

Chen

Chia‐Jung

et al. 2018

Intl Journal of Cancer

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The DNA primase polypeptide 1 (PRIM1) is responsible for synthesizing small RNA primers for Okazaki fragments generated during discontinuous DNA replication. PRIM1 mRNA expression levels in breast tumor samples were detected by real-time PCR analysis. Xenografted tumor model was established to study the carcinogenic role of PRIM1 and its potential therapeutic applications. The average PRIM1 mRNA (copy number × 10 /μg) expression was 4.7-fold higher in tumors than in normal tissue (*p = 0.005, n = 254). PRIM1 was detected preferentially at a higher level (>40-fold) in poorly differentiated tumor tissues (n = 46) compared with more highly differentiated tumors tissues (n = 10) (*p = 0.005). Poor overall survival rate was correlated to the estrogen receptor positive (ER+, n = 20) patients with higher PRIM1 expression when compare to the ER- (n = 10) patients (Chi Square test, p = 0.03). Stable expression of PRIM1-siRNA in the ER+ BT-474 cells-xenograft tumors significantly reduced tumor volume in SCID mice (*p = 0.005). The anti-tumoral effects of inotilone isolated from Phellinus linteus was tested and had significant effects on the inhibition of PRIM1 protein expression in ER+ breast cancer cells. In vivo study was performed by administering inotilone (10 mg/kg, twice a week for 6 weeks), which resulted in significantly reduced BT-474-xenografted tumor growth volume compared with control (n =5 per group, *p < 0.05). This study provides evidences for the prognostic effects of PRIM1 with poor overall survival rate in the ER+ patients and will be valuable to test for therapeutic purpose.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

DNA primase polypeptide 1 (PRIM1) involves in estrogen‐induced breast cancer formation through activation of the G2/M cell cycle checkpoint

Lee

Chen

Chia‐Jung

et al. 2018

Intl Journal of Cancer

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“…The activation of the ATM/ATR–CHK1/2–CDC25C pathway following DNA damage is one of the essential mitotic checkpoint mechanisms [15]. Specifically, CHK2 phosphorylates CDC25C at Ser 216, which subsequently leads to the binding of 14-3-3 proteins and the cytoplasmic sequestration of CDC25C, thereby inhibiting mitotic entry [16].…”

Section: Introductionmentioning

confidence: 99%

The Expression and Clinical Outcome of pCHK2-Thr68 and pCDC25C-Ser216 in Breast Cancer

Jiang¹,

Wang

Zhang³

et al. 2016

IJMS

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Checkpoint kinase 2 (CHK2) and cell division cycle 25C (CDC25C) are two proteins involved in the DNA damage response pathway, playing essential roles in maintaining genome integrity. As one of the major hallmarks of abnormal cellular division, genomic instability occurs in most cancers. In this study, we identified the functional expression of pCHK2-Thr68 and pCDC25C-Ser216 in breast cancer, as well as its association with breast cancer survival. Tissue microarray analysis using immunohistochemistry was constructed to identify the expression of pCHK2-Thr68 and pCDC25C-Ser216 in 292 female breast cancer patients. The relationship among protein expression, clinicopathological factors (e.g., human epidermal growth factor receptor 2 (HER 2), tumor size, tumor-node-metastasis (TNM) classification), and overall survival of the breast cancer tissues were analyzed using Pearson’s χ-square (χ2) test, Fisher’s exact test, multivariate logistic regression and Kaplan–Meier survival analysis. Significantly higher expressions of pCHK2-Thr68 and pCDC25C-Ser216 were observed in the nucleus of the breast cancer cells compared to the paracancerous tissue (pCHK2-Thr68, 20.38% vs. 0%; pCDC25C-Ser216, 82.26% vs. 24.24%). The expression of pCHK2-Thr68 and pCDC25C-Ser216 in breast cancer showed a positive linear correlation (p = 0.026). High expression of pCHK2-Thr68 was associated with decreased patient survival (p = 0.001), but was not an independent prognostic factor. Our results suggest that pCHK2-Thr68 and pCDC25C-Ser216 play important roles in breast cancer and may be potential treatment targets.

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“…rH2AX is the earliest phosphorylation product and also is the characterictic product in DNA damage response [15] [16]. CHK2 is the main protein downstream of ATM, it would be inactive while it phosphorylated to p-CHK2 by ATM and consequently induces cell cycle arrest [17]. Therefore, we have to detect the variation of ATM and series of related proteins in double-stranded DNA damage before we verify the effect of α-pinene on cell cycle.…”

Section: Discussionmentioning

confidence: 99%

Inhibitory Effect of α-Pinene on SGC-7901 Cell Proliferation and the Mechanism of ATM Kinase Signaling Pathway

Zhu¹,

Wei²,

Zhang³

2015

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Objective: To research the inhibitory effect on SGC-7901 cells of α-pinene, and the related mechanism of α-pinene. Methods: Used the MTT method to detect inhibition rate and western blotting to detect the influence on expression of ATM, Phos-S1981ATM, H2AX, γH2AX, CHK2 and p-CHK2, p53 and phos-p53 cell cycle related protein in SGC-7901 cells. Results: The research found α-pinene could inhibit the proliferation of SGC-7901 cells observably in vitro, and the inhibition rate assumes the dependence on concentration; and western blotting results showed that, α-pinene could activate phospho-ATM, increase the amount of γH2AX (p < 0.05, p < 0.05); increase the expression of p-CHK2, p53 and phos-p53 (p < 0.05, p < 0.05, p < 0.05); But there is no significant effect on expression of CHK2 (p > 0.05). Conclusions: α-pinene could inhibit the proliferation of SGC-7901 cells, and by inducing ATM (Ataxia Telangiectasia-Mutated) kinase signal pathway in DNA damage response, activating cell cycle checkpoint, making the cell cycle arrest then exerts its anti-tumor effects.

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Jaridonin-induced G2/M phase arrest in human esophageal cancer cells is caused by reactive oxygen species-dependent Cdc2-tyr15 phosphorylation via ATM–Chk1/2–Cdc25C pathway

Cited by 38 publications

References 31 publications

DNA primase polypeptide 1 (PRIM1) involves in estrogen‐induced breast cancer formation through activation of the G2/M cell cycle checkpoint

DNA primase polypeptide 1 (PRIM1) involves in estrogen‐induced breast cancer formation through activation of the G2/M cell cycle checkpoint

The Expression and Clinical Outcome of pCHK2-Thr68 and pCDC25C-Ser216 in Breast Cancer

Inhibitory Effect of α-Pinene on SGC-7901 Cell Proliferation and the Mechanism of ATM Kinase Signaling Pathway

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