CDC25A inhibition suppresses the growth and invasion of human hepatocellular carcinoma cells

Xu, Xundi; Yamamoto, Hirofumi; Liu, Guoxing; Ito, Yasuhiro; Ngan, Chew Yee; Kondo, Motoi; Nagano, Hiroaki; Dono, Keizo; Sekimoto, Mitsugu; Monden, Morito

doi:10.3892/ijmm.21.2.145

Cited by 16 publications

(17 citation statements)

References 30 publications

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“…Silencing the CDC25A gene significantly inhibited the growth of the xenograft tumors (P<0.05), indicating that cdc25A is a key gene in the development of liver cancer. Xu et al (32) produced a study that used cdc25A antisense to inhibit cdc25A in liver cancer cells, and revealed that cell growth, invasion and cell cycle were inhibited, which was consistent with the results of the present study.…”

Section: Discussionsupporting

confidence: 91%

Silencing CDC25A inhibits the proliferation of liver cancer cells by downregulating IL‑6 in�vitro and in�vivo

et al. 2020

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cell division cycle 25A (cdc25A) is a core regulator of the cell cycle that has a dual-specific phosphatase activity, which is closely associated with the occurrence and development of a tumor, and is overexpressed in liver cancer. However, the molecular mechanism of cdc25A in the development of liver cancer remains unclear. The purpose of the present study was to further investigate the effect of cdc25A on cell proliferation in vitro and in vivo and to investigate whether an interaction exists between cdc25A and interleukin (IL)-6 in liver cancer. An Affymetrix human gene expression profiling chip screened differentially expressed genes in HepG2 cells with silenced cdc25A and the IL-6 signaling pathway was revealed to be significantly inhibited (P<0.05). In the present study, the effects of cdc25A on cell proliferation and migration were analyzed using cell cycle, MTT and Transwell assays. Reverse transcription-quantitative PCR, western blot and immunohistochemistry analyses confirmed that silencing the cdc25A gene downregulated the expression of IL-6 in HepG2 cells and the mRNA and protein expression of IL-1β, mitogen-activated protein kinase kinase kinase 14 (NIK) and nuclear factor-κB (NF-κB), which are regulatory molecules upstream of IL-6. In addition, silencing cdc25A by short hairpin RNA inhibited the development of liver cancer xenograft tumor types in nude mice, and decreased the expression of IL-1β, NIK, NF-κB and IL-6 in xenograft tumor types. In conclusion, silencing CDC25A significantly inhibited the proliferation of liver cancer cells in vitro and in vivo, potentially via an interaction with IL-6 through the downregulation of the IL-1β/NIK/NF-κB signaling axis.

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Section: Discussionsupporting

confidence: 91%

Silencing CDC25A inhibits the proliferation of liver cancer cells by downregulating IL‑6 in�vitro and in�vivo

et al. 2020

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“…In addition, overexpression of CDC25B in the mammary glands of mice increases the proliferation of mammary epithelial cells and hyperplasia, which induces tumor growth when also challenged with the carcinogen 9,10-dimethyl-1,2-benzanthracene [7,8] . Conversely, downregulating the expression of CDC25B by microinjecting antibodies against CDC25B causes G2 arrest, whereas RNA interference against CDC25A causes G1 arrest and significant inhibition of cancer cell invasion [9,10] . These findings in turn make CDC25 A and B ideal targets for a new anticancer therapy.…”

Section: Introductionmentioning

confidence: 99%

LGH00031, a novel ortho-quinonoid inhibitor of cell division cycle 25B, inhibits human cancer cells via ROS generation

et al. 2009

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Aim: To discover novel cell division cycle 25 (CDC25) B inhibitors and elucidate the mechanisms of inhibition in cancer cells. Methods: Cell growth inhibition was detected by MTT assay, the cell cycle was analyzed by flow cytometry, and protein expression and phosphorylation was examined by Western blot analysis. Results:LGH00031 inhibited CDC25B irreversibly in vitro in a dose-dependent manner, and impaired the proliferation of tumor cell lines. In synchronized HeLa cells, LGH00031 delayed the cell cycle progression at the G 2 /M phase. LGH00031 increased cyclindependent kinase 1 (CDK1) tyrosine 15 phosphorylation and cyclin B1 protein level. The activity of LGH00031 against CDC25B in vitro relied on the existence of 1,4-dithiothreitol (DTT) or dihydrolipoic acid and oxygen. The oxygen free radical scavenger catalase and superoxide dismutase reduced the inactivation of CDC25 by LGH00031, confirming that reactive oxygen species (ROS) mediate the inactivation process in vitro.LGH00031 accelerated cellular ROS production in a dose-dependent manner, and N-acetyl cysteine (NAC) markedly decreased the ROS production induced by LGH00031. Correspondingly, the LGH00031-induced decrease in cell viability and cell cycle arrest, cyclin B1 protein level, and phosphorylation of CDK1 tyrosine 15 were also rescued by NAC that decreased ROS production. Conclusion: The activity of LGH00031 at the molecular and cellular level is mediated by ROS.

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“…CDC25a, a member of the CDC25 family of phosphatases, is required for progression from G1 to the S phase of the cell cycle [51, 52]. Interfering with CDC25a suppresses the growth and invasion in tumor cells [51, 53, 54]. Our results indicated that enforced LRRC4 expression prevents the activation of ERK downstream transcription factors to inhibit glioblastoma cell proliferation and invasion.…”

Section: Discussionmentioning

confidence: 76%

The D Domain of LRRC4 anchors ERK1/2 in the cytoplasm and competitively inhibits MEK/ERK activation in glioma cells

et al. 2016

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BackgroundAs a well-characterized key player in various signal transduction networks, extracellular-signal-regulated kinase (ERK1/2) has been widely implicated in the development of many malignancies. We previously found that Leucine-rich repeat containing 4 (LRRC4) was a tumor suppressor and a negative regulator of the ERK/MAPK pathway in glioma tumorigenesis. However, the precise molecular role of LRRC4 in ERK signal transmission is unclear.MethodsThe interaction between LRRC4 and ERK1/2 was assessed by co-immunoprecipitation and GST pull-down assays in vivo and in vitro. We also investigated the interaction of LRRC4 and ERK1/2 and the role of the D domain in ERK activation in glioma cells.ResultsHere, we showed that LRRC4 and ERK1/2 interact via the D domain and CD domain, respectively. Following EGF stimuli, the D domain of LRRC4 anchors ERK1/2 in the cytoplasm and abrogates ERK1/2 activation and nuclear translocation. In glioblastoma cells, ectopic LRRC4 expression competitively inhibited the interaction of endogenous mitogen-activated protein kinase (MEK) and ERK1/2. Mutation of the D domain decreased the LRRC4-mediated inhibition of MAPK signaling and its anti-proliferation and anti-invasion roles.ConclusionsOur results demonstrated that the D domain of LRRC4 anchors ERK1/2 in the cytoplasm and competitively inhibits MEK/ERK activation in glioma cells. These findings identify a new mechanism underlying glioblastoma progression and suggest a novel therapeutic strategy by restoring the activity of LRRC4 to decrease MAPK cascade activation.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-016-0355-1) contains supplementary material, which is available to authorized users.

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CDC25A inhibition suppresses the growth and invasion of human hepatocellular carcinoma cells

Cited by 16 publications

References 30 publications

Silencing CDC25A inhibits the proliferation of liver cancer cells by downregulating IL‑6 in�vitro and in�vivo

Silencing CDC25A inhibits the proliferation of liver cancer cells by downregulating IL‑6 in�vitro and in�vivo

LGH00031, a novel ortho-quinonoid inhibitor of cell division cycle 25B, inhibits human cancer cells via ROS generation

The D Domain of LRRC4 anchors ERK1/2 in the cytoplasm and competitively inhibits MEK/ERK activation in glioma cells

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