scholarly journals Epigenetic Silencing of TMEM176A Activates ERK Signaling in Human Lung Cancer

2020 ◽  
pp. 1-11
Author(s):  
Liming Hu ◽  
Fuyou Zhou ◽  
Hongxia Li ◽  
James G Herman ◽  
Liming Hu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
Promoter Region ◽  
Human Lung ◽  
Lung Cancer Cells ◽  
Erk Signaling ◽  
Human Lung Cancer ◽  
Lung Cancers ◽  
H460 Cells ◽  
Partially Methylated

Background: The function of TMEM176A in human lung cancer remains to be elucidated. Materials & Methods: Nine cell lines and 123 cases of lung cancers were employed. Results: TMEM176A was highly expressed in H727 cells, reduced expression was observed in A549, H446 and H460 cells, loss of expression was found in H157, H1563, H358, H1299 and H23 cells. TMEM176A was unmethylated in H727 cells, partially methylated in A549, H446 and H460 cells, and fully methylated in H157, H1563, H358, H1299 and H23 cells. Loss of/reduced expression of TMEM176A is correlated to promoter region methylation. Restoration of TMEM176A expression was induced by 5-AZA-2- deoxycytidine in complete methylated cells, increased expression of TMEM176A was observed in partially methylated cells. These results suggest that TMEM176A is regulated by promoter region methylation in lung cancer cells. TMEM176A was methylated in 53.66% (66/123) of non-small cell lung cancers (NSCLCs) samples. Reduced expression of TMEM176A was associated with promoter region methylation in 40 cases of matched primary NSCLCs and adjacent tissue samples (P<0.05). TMEM176A expression induced cell apoptosis, inhibited colony formation, cell proliferation, migration and invasion. Conclusion: Methylation of TMEM176A activated ERK signaling in lung cancer cells. TMEM176A suppressed human lung cancer cell xenograft growth in mice.

scholarly journals CYLD Promotes TNF-α-Induced Cell Necrosis Mediated by RIP-1 in Human Lung Cancer Cells

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Xing Lin ◽  
Qianshun Chen ◽  
Chen Huang ◽  
Xunyu Xu
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
Human Lung ◽  
A549 Cells ◽  
Lung Cancer Cells ◽  
Human Lung Cancer ◽  
Cell Necrosis ◽  
Cancer Pathogenesis ◽  
Human Lung Cancer Cells ◽  
H460 Cells

Lung cancer is one of the most common cancers in the world. Cylindromatosis (CYLD) is a deubiquitination enzyme and contributes to the degradation of ubiquitin chains on RIP1. The aim of the present study is to investigate the levels of CYLD in lung cancer patients and explore the molecular mechanism of CYLD in the lung cancer pathogenesis. The levels of CYLD were detected in human lung cancer tissues and the paired paracarcinoma tissues by real-time PCR and western blotting analysis. The proliferation of human lung cancer cells was determined by MTT assay. Cell apoptosis and necrosis were determined by FACS assay. The results demonstrated that low levels of CYLD were detected in clinical lung carcinoma specimens. Three pairs of siRNA were used to knock down the endogenous CYLD in lung cancer cells. Knockdown of CYLD promoted cell proliferation of lung cancer cells. Otherwise overexpression of CYLD induced TNF-α-induced cell death in A549 cells and H460 cells. Moreover, CYLD-overexpressed lung cancer cells were treated with 10 μM of z-VAD-fmk for 12 hours and the result revealed that TNF-α-induced cell necrosis was significantly enhanced. Additionally, TNF-α-induced cell necrosis in CYLD-overexpressed H460 cells was mediated by receptor-interacting protein 1 (RIP-1) kinase. Our findings suggested that CYLD was a potential target for the therapy of human lung cancers.

scholarly journals P3.01-041 Anti-Cancer Effect of Hyperoxia on Human Lung Cancer Cells through Oxidative Stress Mediated ERK Signaling

2017 ◽  
Vol 12 (1) ◽  
pp. S1144-S1145
Author(s):  
Hyonsoo Joo ◽  
Jin Young Mo ◽  
In Kyoung Kim ◽  
Hyeon Hui Kang ◽  
Sang Haak Lee
Keyword(s):  
Oxidative Stress ◽  
Lung Cancer ◽  
Cancer Cells ◽  
Human Lung ◽  
Lung Cancer Cells ◽  
Erk Signaling ◽  
Human Lung Cancer ◽  
Anti Cancer ◽  
Human Lung Cancer Cells

scholarly journals Polo-like kinase 4 inhibition produces polyploidy and apoptotic death of lung cancers

2018 ◽  
Vol 115 (8) ◽  
pp. 1913-1918 ◽  
Author(s):  
Masanori Kawakami ◽  
Lisa Maria Mustachio ◽  
Lin Zheng ◽  
Yulong Chen ◽  
Jaime Rodriguez-Canales ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
Dna Content ◽  
Human Lung ◽  
Lung Cancer Cells ◽  
Human Lung Cancer ◽  
Normal Lung ◽  
Lung Cancers ◽  
Centriole Duplication ◽  
Apoptotic Death

Polo-like kinase 4 (PLK4) is a serine/threonine kinase regulating centriole duplication. CFI-400945 is a highly selective PLK4 inhibitor that deregulates centriole duplication, causing mitotic defects and death of aneuploid cancers. Prior work was substantially extended by showing CFI-400945 causes polyploidy, growth inhibition, and apoptotic death of murine and human lung cancer cells, despite expression of mutated KRAS or p53. Analysis of DNA content by propidium iodide (PI) staining revealed cells with >4N DNA content (polyploidy) markedly increased after CFI-400945 treatment. Centrosome numbers and mitotic spindles were scored. CFI-400945 treatment produced supernumerary centrosomes and mitotic defects in lung cancer cells. In vivo antineoplastic activity of CFI-400945 was established in mice with syngeneic lung cancer xenografts. Lung tumor growth was significantly inhibited at well-tolerated dosages. Phosphohistone H3 staining of resected lung cancers following CFI-400945 treatment confirmed the presence of aberrant mitosis. PLK4 expression profiles in human lung cancers were explored using The Cancer Genome Atlas (TCGA) and RNA in situ hybridization (RNA ISH) of microarrays containing normal and malignant lung tissues. PLK4 expression was significantly higher in the malignant versus normal lung and conferred an unfavorable survival (P < 0.05). Intriguingly, cyclin dependent kinase 2 (CDK2) antagonism cooperated with PLK4 inhibition. Taken together, PLK4 inhibition alone or as part of a combination regimen is a promising way to combat lung cancer.

scholarly journals S-phase kinase-associated protein 2 positively controls mitotic arrest deficient 2 in lung cancer cells

2016 ◽  
Author(s):  
Tonghai Huang ◽  
Lin Yang ◽  
Guangsuo Wang ◽  
Guanggui Ding ◽  
Bin Peng ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
Spindle Assembly Checkpoint ◽  
Human Lung ◽  
Mitotic Arrest ◽  
S Phase ◽  
Lung Cancer Cells ◽  
Human Lung Cancer ◽  
Lung Cancers ◽  
Protein Levels

Background. Mitotic arrest deficient 2 (Mad2) is a key component of spindle assembly checkpoint and overexpressed in human lung cancers, but the mechanism of the deregulation of Mad2 in lung cancer is largely unknown. We aim to investigate the regulation of Mad2 by S-phase kinase-associated protein 2 (Skp2) in human lung cancer cells. Methods. Human lung cancer A549 and NCI-H1975 cells were transfected with MAD2 and SKP2 siRNAs or plasmids to silence or overexpress MAD2 and SKP2. Flavopiridol and HLM006474 were used to inhibit cyclin dependent kinases (CDKs) and E2F1, respectively. mRNA and protein levels were determined by real-time PCR and Western blot, respectively. Cell cycle progression was assayed by flow cytometery. Results. Knockdown of Skp2 by siRNA decreased Mad2 mRNA and protein levels in A549 and NCI-H1299 cells, accompanied with upregulation of p27 but decrease of the phosphorylation of retinoblastoma (Rb). In contrast, ectopic overexpression of Skp2 increased Mad2 mRNA and protein levels and phosphorylation of Rb, while decreased p27. Pharmacological inhibition of CDK1/2 by flavopiridol or E2F1 with HLM006474 led to downregulation of Mad2 expression, and prevented the increase of Mad2 expression by Skp2. Accordingly, silencing of either Mad2 or Skp2 impaired the mitosis arrest in response to nocadazole. Conclusion. SKP2 positively regulates the gene expression of MAD2 through p27-CDKs-E2F1 signaling pathway, suggesting that deregulation of Skp2 may lead to upregulation of Mad2 via enhancing the activity of CDKs in human lung cancers. Our findings may provide an explanation of the simultaneous upregulation of MAD2 and SKP2 in lung cancer and potential targets for the development of molecular targeted therapy for lung cancers.

scholarly journals S-phase kinase-associated protein 2 positively controls mitotic arrest deficient 2 in lung cancer cells

2016 ◽  
Author(s):  
Tonghai Huang ◽  
Lin Yang ◽  
Guangsuo Wang ◽  
Guanggui Ding ◽  
Bin Peng ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
Spindle Assembly Checkpoint ◽  
Human Lung ◽  
Mitotic Arrest ◽  
S Phase ◽  
Lung Cancer Cells ◽  
Human Lung Cancer ◽  
Lung Cancers ◽  
Protein Levels

Background. Mitotic arrest deficient 2 (Mad2) is a key component of spindle assembly checkpoint and overexpressed in human lung cancers, but the mechanism of the deregulation of Mad2 in lung cancer is largely unknown. We aim to investigate the regulation of Mad2 by S-phase kinase-associated protein 2 (Skp2) in human lung cancer cells. Methods. Human lung cancer A549 and NCI-H1975 cells were transfected with MAD2 and SKP2 siRNAs or plasmids to silence or overexpress MAD2 and SKP2. Flavopiridol and HLM006474 were used to inhibit cyclin dependent kinases (CDKs) and E2F1, respectively. mRNA and protein levels were determined by real-time PCR and Western blot, respectively. Cell cycle progression was assayed by flow cytometery. Results. Knockdown of Skp2 by siRNA decreased Mad2 mRNA and protein levels in A549 and NCI-H1299 cells, accompanied with upregulation of p27 but decrease of the phosphorylation of retinoblastoma (Rb). In contrast, ectopic overexpression of Skp2 increased Mad2 mRNA and protein levels and phosphorylation of Rb, while decreased p27. Pharmacological inhibition of CDK1/2 by flavopiridol or E2F1 with HLM006474 led to downregulation of Mad2 expression, and prevented the increase of Mad2 expression by Skp2. Accordingly, silencing of either Mad2 or Skp2 impaired the mitosis arrest in response to nocadazole. Conclusion. SKP2 positively regulates the gene expression of MAD2 through p27-CDKs-E2F1 signaling pathway, suggesting that deregulation of Skp2 may lead to upregulation of Mad2 via enhancing the activity of CDKs in human lung cancers. Our findings may provide an explanation of the simultaneous upregulation of MAD2 and SKP2 in lung cancer and potential targets for the development of molecular targeted therapy for lung cancers.

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