The depletion of ATM inhibits colon cancer proliferation and migration via B56γ2-mediated Chk1/p53/CD44 cascades

Li, Rui; Tang, Junhua; Ding, Chengcheng; Liang, Weicheng; Zhang, Li; Chen, Tianke; Xiong, Yan; Dai, Xuemei; Li, Wenfeng; Xu, Yunsheng; Jin, Haixia; Lu, Lijuan; Liao, Wanqin; Lu, Xincheng

doi:10.1016/j.canlet.2016.12.040

Cited by 14 publications

(11 citation statements)

References 36 publications

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“…Recent studies suggest that DNA damage-independent ATM enhances metastasis via suppressing B56γ2 in the colon 29 or upregulating interleukin (IL)-8 in breast cancer 30 . To address whether citrate accumulation was related to B56γ2 or IL-8, shRNA against B56γ2 or exogenous IL-8 was transfected into hypoxic BT549 and Hs578T cells.…”

Section: Resultsmentioning

confidence: 99%

RETRACTED ARTICLE: Intracellular citrate accumulation by oxidized ATM-mediated metabolism reprogramming via PFKP and CS enhances hypoxic breast cancer cell invasion and metastasis

et al. 2019

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Citrate, a substance being related to de novo fatty acid synthesis and tricarboxylic acid (TCA) cycle, has a pivotal role in cell survival. However, the molecular mechanisms that regulate intracellular citrate in triple-negative breast cancer (TNBC), especially under hypoxic condition, remain poorly understood. Here we find that hypoxia (1% O 2 ) induces DNA damage-independent ATM activation (oxidized ATM) and suppression of oxidized ATM reduces intracellular citrate via decreasing the levels of phosphofructokinase (PFKP) and citrate synthase (CS), two key glucose metabolism-associated enzymes. Mechanistically, PFKP is regulated by HIF1A at the translational level, whereas CS is of posttranscriptional regulation by UBR5-mediated ubiquitination. Interestingly, accumulation of citrate in cytoplasm or exogenous citrate significantly enhances cell migration, invasion, and metastasis of hypoxic TNBC cells in vitro and in mice xenografts. The underlying mechanism mainly involves citrate-stimulated activation of the AKT/ERK/MMP2/9 signaling axis. Our findings unravel a novel function of oxidized ATM in promoting migration, invasion, and metastasis of TNBC.

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Section: Resultsmentioning

confidence: 99%

RETRACTED ARTICLE: Intracellular citrate accumulation by oxidized ATM-mediated metabolism reprogramming via PFKP and CS enhances hypoxic breast cancer cell invasion and metastasis

et al. 2019

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“…Chen S [22] et al reported that ATM was involved in EMT in pancreatic cancer by regulation of long non-coding RNA ANRIL. Liu R [23] et al reported that depletion of ATM inhibited colon cancer proliferation and migration via Chk1/P53/CD44 cascades. In this study, we for the first time demonstrated that increased ATM expression contribute to increased EMT and metastatic potential in cisplatin-resistant NSCLC cells.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of ATM reverses EMT and decreases metastatic potential of cisplatin-resistant lung cancer cells through JAK/STAT3/PD-L1 pathway

Shen

et al. 2019

J Exp Clin Cancer Res

130

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Background The cisplatin-resistance is still a main course for chemotherapy failure of lung cancer patients. Cisplatin-resistant cancer cells own higher malignance and exhibited increased metastatic ability, but the mechanism is not clear. In this study, we investigated the effects of Ataxia Telangiectasia Mutated (ATM) on lung cancer metastasis. Materials and methods Cisplatin-resistant A549CisR and H157CisR cell line were generated by long-term treating parental A549 and H157 cells (A549P and H157P) with cisplatin. Cell growth, cell migration and cell invasion were determined. Gene expressions were determined by Western Blot and qPCR. Tumor metastasis was investigated using a xenograft mouse model. Results The IC50 of the cisplatin-resistant cells (A549CisR and H157CisR cells) to cisplatin was 6–8 higher than parental cells. The A549CisR and H157CisR cells expressed lower level of E-cadherin and higher levels of N-cadherin, Vimentin and Snail compared to the parental A549P and H157P cells, and exhibited stronger capabilities of metastatic potential compared to the parental cells. The ATM expression was upregulated in A549CisR and H157CisR cells and cisplatin treatment also upregulated expression of ATM in parental cells, The inhibition of ATM by using specific ATM inhibitor CP466722 or knock-down ATM by siRNA suppressed Epithelial-to-Mesenchymal transition (EMT) and metastatic potential of A549CisR and H157CisR cells. These data suggest that ATM mediates the cisplatin-resistance in lung cancer cells. Expressions of JAK 1,2, 、 STAT 3 、PD-L1 and ATM were increased in A549CisR and H157CisR cells and could by induced by cisplatin in parental lung cancer cells. Interestedly, ATM upregulated PD-L1 expression via JAK 1,2 /STAT 3 pathway and inhibition of ATM decreased JAK/STAT3 signaling and decreased PD-L1 expression. The treatment of PD-L1 neutralizing Ab reduced EMT and cell invasion. Inhibition of JAK 1,2 /STAT 3 signaling by specific inhibitors suppressed ATM-induced PD-L1 expression, EMT and cell invasion. Importantly, inhibition of ATM suppressed EMT and tumor metastasis in cisplatin-resistant lung cancer cells in an orthotopic xenograft mouse model. Conclusions Our results show that ATM regulates PD-L1 expression through activation of JAK/STAT3 signaling in cisplatin-resistant cells. Overexpression of ATM contributes to cisplatin-resistance in lung cancer cells. Inhibition of ATM reversed EMT and inhibited cell invasion and tumor metastasis. Thus, ATM may be a potential target for the treatment of cisplatin-resistant lung cancer. Electronic supplementary material The online version of this article (10.1186/s13046-019-1161-8) contains supplementary material, which is available to authorized users.

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“…Another study reported that the ATM inhibitor KU-55933 can hinder cancer cell proliferation by inducing G1 blockade and thereby triggering apoptosis in cancer cells [39]. Liu R et al also revealed that ATM deletion could dramatically decrease the proliferation, migration and invasion of colon cancer cells [40], which could also lead to a remarkable reduction in migration and epithelial-mesenchymal transition (EMT) in prostate cancer cells [41]. In our experiment, ATM was confirmed to be the downstream target gene of miR-203a-3p through bioinformatics prediction and a dual-luciferase reporter gene assay.…”

Section: Discussionmentioning

confidence: 99%

MiR-203a-3p regulates the biological behaviors of ovarian cancer cells through mediating the Akt/GSK-3β/Snail signaling pathway by targeting ATM

et al. 2019

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Objective To investigate whether miR-203a-3p can regulate the biological behaviors of ovarian cancer cells by targeting ATM to affect the Akt/GSK-3β/Snail signaling pathway. Methods The expression levels of miR-203a-3p and ATM were detected by qRT-PCR, immunohistochemical staining and Western blotting in ovarian cancer tissues and adjacent normal tissues obtained from 152 subjects. A dual-luciferase reporter gene assay was performed to verify the relationship between miR-203a-3p and ATM. Human ovarian cancer cell lines (A2780 and SKOV3) were used to generate the Blank, miR-NC, miR-203a-3p mimic, Control siRNA, ATM siRNA, and miR-203a-3p inhibitor + ATM siRNA groups. The biological behaviors of ovarian cancer cells were evaluated by CCK-8, wound healing, and Transwell invasion assays, annexin V-FITC/PI staining and flow cytometry. The levels of Akt/GSK-3β/Snail pathway-related proteins were assessed by Western blotting. Results Ovarian cancer tissues showed lower miR-203a-3p levels and higher ATM levels than adjacent normal tissues, both of which were associated with the FIGO stage, grade and prognosis of ovarian cancer. As confirmed by a dual-luciferase reporter gene assay, miR-203a-3p could target ATM . Furthermore, the miR-203a-3p mimic had multiple effects, including the inhibition of the proliferation, invasion and migration of A2780 and SKOV3 cells, the promotion of cell apoptosis, the arrest of the cell cycle at the G1 phase, and the blockage of the Akt/GSK-3β/Snail signaling pathway. ATM siRNA had similar effects on the biological behaviors of ovarian cancer cells, and these effects could be reversed by a miR-203a-3p inhibitor. Conclusion miR-203a-3p was capable of hindering proliferation, migration, and invasion and facilitating the apoptosis of ovarian cancer cells through its modulation of the Akt/GSK-3β/Snail signaling pathway by targeting ATM, and therefore it could serve as a potential therapeutic option for ovarian cancer.

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The depletion of ATM inhibits colon cancer proliferation and migration via B56γ2-mediated Chk1/p53/CD44 cascades

Cited by 14 publications

References 36 publications

RETRACTED ARTICLE: Intracellular citrate accumulation by oxidized ATM-mediated metabolism reprogramming via PFKP and CS enhances hypoxic breast cancer cell invasion and metastasis

RETRACTED ARTICLE: Intracellular citrate accumulation by oxidized ATM-mediated metabolism reprogramming via PFKP and CS enhances hypoxic breast cancer cell invasion and metastasis

Inhibition of ATM reverses EMT and decreases metastatic potential of cisplatin-resistant lung cancer cells through JAK/STAT3/PD-L1 pathway

MiR-203a-3p regulates the biological behaviors of ovarian cancer cells through mediating the Akt/GSK-3β/Snail signaling pathway by targeting ATM

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