Activation of the ATM-Snail pathway promotes breast cancer metastasis

Sun, Mianen; Guo, Xiaojing; Qian, Xiaolong; Wang, Haibo; Yang, Chunying; Brinkman, Kathryn L.; Serrano-González, Mónica; Jope, Richard S.; Zhou, Binhua P.; Engler, David; Zhan, Ming; Wong, Stephen T.C.; Fu, Li; Xu, Bo

doi:10.1093/jmcb/mjs048

Cited by 99 publications

(95 citation statements)

References 43 publications

(49 reference statements)

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“…Notably, Snail is a substrate of the major radiation-induced kinase ATM, and this phosphorylation is involved in radiosensitivity. 49 Another intriguing aspect of our results is the link between EMT and stem-like cell traits. Epithelial cancer cells undergoing EMT exhibit also features of stemness, 50,51 and Snail induces both EMT and stem cell-like features in squamous cell carcinoma.…”

Section: Discussionmentioning

confidence: 91%

“…The radiationinduced phenotypic heterogeneity, we report, might reflect transient cellular plasticity as well as stress-evoked responses of preexistent subsets cells seen in the parental DU145 and PC-3 cell populations. [40][41][42][43][44][45][46][47][48][49][50][51][52] Ionizing radiation can promote traits of EMT in normal human mammary epithelium, 41 lung carcinoma 42,43 and colorectal cancer cells. 44 Furthermore, besides their role in E-cadherin repression, 45,46 Slug and Snail have been implicated in radioresistance-associated EMT.…”

Section: Discussionmentioning

confidence: 99%

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Radiotherapy-induced plasticity of prostate cancer mobilizes stem-like non-adherent, Erk signaling-dependent cells

et al. 2014

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Fractionated ionizing radiation combined with surgery or hormone therapy represents the first-choice treatment for medium to high-risk localized prostate carcinoma. One of the main reasons for the failure of radiotherapy in prostate cancer is radioresistance and further dissemination of surviving cells. In this study, exposure of four metastasis-derived human prostate cancer cell lines (DU145, PC-3, LNCaP and 22RV1) to clinically relevant daily fractions of ionizing radiation (35 doses of 2 Gy) resulted in generation of two radiation-surviving populations: adherent senescent-like cells expressing common senescenceassociated markers and non-adherent anoikis-resistant stem cell-like cells with active Notch signaling and expression of stem cell markers CD133, Oct-4, Sox2 and Nanog. While a subset of the radiation-surviving adherent cells resumed proliferation shortly after completion of the irradiation regimen, the non-adherent cells started to proliferate only on their reattachment several weeks after the radiation-induced loss of adhesion. Like the parental non-irradiated cells, radiation-surviving re-adherent DU145 cells were tumorigenic in immunocompromised mice. The radiation-induced loss of adhesion was dependent on expression of Snail, as siRNA/shRNA-mediated knockdown of Snail prevented cell detachment. On the other hand, survival of the non-adherent cells required active Erk signaling, as chemical inhibition of Erk1/2 by a MEK-selective inhibitor or Erk1/2 knockdown resulted in anoikis-mediated death in the non-adherent cell fraction. Notably, whereas combined inhibition of Erk and PI3K-Akt signaling triggered cell death in the non-adherent cell fraction and blocked proliferation of the adherent population of the prostate cancer cells, such combined treatment had only marginal if any impact on growth of control normal human diploid cells. These results contribute to better understanding of radiation-induced stress response and heterogeneity of human metastatic prostate cancer cells, document treatment-induced plasticity and phenotypically distinct cell subsets, and suggest the way to exploit their differential sensitivity to radiosensitizing drugs in overcoming radioresistance. Cell Death and Differentiation (2015) 22, 898-911; doi:10.1038/cdd.2014.97; published online 11 July 2014Prostate carcinoma (CaP) is the most frequent type of cancer in men, and the sixth cause of cancer-associated death in men worldwide. 1 Despite the advances in diagnosis and therapy of CaP, the mortality has remained almost unchanged for the last decades. Currently, the most successful treatment for localized CaP is prostatectomy with postoperative fractionated radiotherapy, significantly improving metastasis-free and overall survival, where the median of a 15-year survival is around 47% of patients. 2,3 The rest of the patients develop a metastatic disease that is incurable due to the resistance of CaP to androgen ablation, radiotherapy and chemotherapy. Therefore, understanding the mechanisms of radioresistance and chemoresista...

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Radiotherapy-induced plasticity of prostate cancer mobilizes stem-like non-adherent, Erk signaling-dependent cells

et al. 2014

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“…In breast tumor tissues, there was a correlation of ATM-induced phosphorylation of Snail with lymphnode metastasis. Phosphorylation at Ser 100 stabilize Snail as well as promote invasion and cancer metastasis, which is important for cell survival in response to ionizing irradiation [29,30]. The identification of ZEB1 as another ATM substrate for phosphorylation and the mechanism behind further confirmed the association between radioresistance and EMT process [31].…”

Section: Phosphorylation Of Snailmentioning

confidence: 75%

Post-translational modifications of EMT transcriptional factors in cancer metastasis

2016

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Metastasis is an important reason for death of cancer patients which characterized as the formation of secondary cancers at distant sites. Epithelial– mesenchymal transition (EMT) is a dynamic process that appear to facilitate tumor metastasis in various cancers by switching epithelial cells into mesenchymal properties. Although previous investigation suggested a key role of EMT transcriptional factors in suppression of E-cadherin, the association of these factors with other cellular regulators in cancer metastasis need to be fully elucidated. Post-translational modifications (PTMs), such as acetylation and phosphorylation, have emerged as an important mechanism to modulate biological behavior of substrate proteins. In this review, we summarized protein modification and subsequent function changes of Snail, Twist and ZEB, as well as their influence on tumor progression. Acetylation of EMT transcriptional factors usually cause nuclear localization and/or protein stabilization thus contribute to E-cadherin repression. Besides, Twist and ZEB were phosphorylated by diverse kinases to promote metastasis in many cancers, while Snail was negatively regulated by phosphorylation to degradation. Then, the potential of therapy for metastasis by targeting PTMs-involved regulation of EMT transcriptional factors were discussed.

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“…Previous studies have found that ATM and AKT1 are associated with the progress of multiple types of cancers [14][15][16]. For instance, Sun et al found that ATM can involve in the tumor metastasis thorough regulation of Snail in breast cancer [17]. Rachelle et al found that AKT1 promotes mammary tumor induction but not metastasis [16].…”

Section: Discussionmentioning

confidence: 99%

Signature consist of nine differentially methylated gene pairs to predict the prognosis for stage II colorectal cancer patients

Zeng¹,

Li²,

Wei³

et al. 2018

Oncotarget

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Colorectal cancer (CRC) is the third most commonly malignance cancer worldwide. The quality of life and life expectancy of CRC survivors are seriously impacted by the recurrence after resection surgery. Therefore, there is a need to develop a reliable signature to predict the recurrence after resection surgery in CRC patients. Epigenetic alterations, especially gene methylation, have been found highly related to the metastasis of tumors. However, limited evidence is available for CRC patients. Moreover, there remains a knowledge gap of a comprehensive view of gene methylation in stage II CRC. In this study, we conducted and validated a differentially methylated 9-gene-pair prognosis signature to predict recurrence after resection surgery in stage II CRC patients. In addition, we use Univariable and Multivariable Cox regression to estimate the association between relapse free survival times in relation to each candidate gene pairs and the 9-gene-pair score. Moreover, the network analysis found 8 hub genes, including NDRG4 and BMP3, out of all candidate genes have large degree of interactions in the protein-protein interaction network. Seven hub genes have been found associated with CRC progression. Furthermore, the function enrichment analysis suggested that differentially methylated genes were mostly enriched in the cell cycle pathway. In summary, a 9-gene-pair signature was developed and validated in this study. The signatures identified in this study have the potential to be applied in the prognosis of post-surgery recurrence in the stage II CRC patents.

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Activation of the ATM-Snail pathway promotes breast cancer metastasis

Cited by 99 publications

References 43 publications

Radiotherapy-induced plasticity of prostate cancer mobilizes stem-like non-adherent, Erk signaling-dependent cells

Radiotherapy-induced plasticity of prostate cancer mobilizes stem-like non-adherent, Erk signaling-dependent cells

Post-translational modifications of EMT transcriptional factors in cancer metastasis

Signature consist of nine differentially methylated gene pairs to predict the prognosis for stage II colorectal cancer patients

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