scholarly journals Glycogen Synthase Kinase 3 Protein Kinase Activity Is Frequently Elevated in Human Non-Small Cell Lung Carcinoma and Supports Tumour Cell Proliferation

PLoS ONE ◽  
2014 ◽  
Vol 9 (12) ◽  
pp. e114725 ◽  
Author(s):  
Emma E. Vincent ◽  
Douglas J. E. Elder ◽  
Linda O′Flaherty ◽  
Olivier E. Pardo ◽  
Piotr Dzien ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Protein Kinase ◽  
Kinase Activity ◽  
Glycogen Synthase ◽  
Small Cell Lung Carcinoma ◽  
Small Cell ◽  
Glycogen Synthase Kinase 3 ◽  
Protein Kinase Activity ◽  
Small Cell Lung ◽  
Cell Lung Carcinoma

scholarly journals Prognostic Impact of PCK1 Protein Kinase Activity-Dependent Nuclear SREBP1 Activation in Non-Small-Cell Lung Carcinoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Fei Shao ◽  
Xueli Bian ◽  
Juhong Wang ◽  
Daqian Xu ◽  
Wei Guo ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Lung Carcinoma ◽  
Kinase Activity ◽  
Small Cell Lung Carcinoma ◽  
Small Cell ◽  
Protein Kinase Activity ◽  
Small Cell Lung ◽  
Cell Lung Carcinoma ◽  
Expression Levels ◽  
Human Nsclc

Metabolic enzymes can perform non-metabolic functions and play critical roles in the regulation of a variety of important cellular activities. Phosphoenolpyruvate carboxykinase 1 (PCK1), a gluconeogenesis enzyme, was recently identified as an AKT-regulated protein kinase that phosphorylates INSIG1/2 to promote nuclear SREBP1-dependent lipogenesis. However, the relationship of this regulation with the progression of non-small-cell lung carcinoma (NSCLC) is unclear. Here, we demonstrate that epidermal growth factor receptor (EGFR) activation induces AKT-dependent PCK1 pS90, PCK1-mediated INSIG1 pS207/INSIG2 pS151, and nuclear SREBP1 accumulation in NSCLC cells. In addition, the expression levels of AKT pS473, PCK1 pS90, INSIG1 pS207/INSIG2 pS151, and nuclear SREBP1 are higher in 451 analyzed human NSCLC specimens than in their adjacent normal tissues and positively correlated with each other in the tumor specimens. Furthermore, the expression levels of PCK1 pS90, INSIG1 pS207/INSIG2 pS151, and nuclear SREBP1 are associated with TNM stage and progression in NSCLC. Importantly, levels of PCK1 pS90 or INSIG1 pS207/INSIG2 pS151 are positively correlated with poor prognosis in NSCLC patients, and the combined expression value of the PCK1 and INSIG1/2 phosphorylation has a better prognostic value than that of each individual protein phosphorylation value and is an independent prognostic marker for NSCLC. These findings reveal the role of PCK1-mediated nuclear SREBP1 activation in NSCLC progression and highlight the potential to target the protein kinase activity of PCK1 for the diagnosis and treatment of human NSCLC.

scholarly journals CELF2 suppresses non-small cell lung carcinoma growth by inhibiting the PREX2-PTEN interaction

2019 ◽  
Vol 41 (3) ◽  
pp. 377-389 ◽  
Author(s):  
Yiu To Yeung ◽  
Suyu Fan ◽  
Bingbing Lu ◽  
Shuying Yin ◽  
Sen Yang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Phosphatase Activity ◽  
Lung Carcinoma ◽  
Rna Binding ◽  
Small Cell Lung Carcinoma ◽  
Small Cell ◽  
Low Grade ◽  
Small Cell Lung ◽  
Cell Lung Carcinoma ◽  
Human Cancers

Abstract The phosphoinositide 3-kinase (PI3-K)/Akt signaling pathway is important in the regulation of cell proliferation through its production of phosphatidylinositol 3,4,5-triphosphate (PIP3). Activation of this pathway is frequently observed in human cancers, including non-small cell lung carcinoma. The PI3-K/Akt pathway is negatively regulated by the dual-specificity phosphatase and tensin homolog (PTEN) protein. PTEN acts as a direct antagonist of PI3-K by dephosphorylating PIP3. Studies have shown that PTEN phosphatase activity is inhibited by PREX2, a guanine nucleotide exchanger factor (GEF). Multiple studies revealed that CELF2, an RNA binding protein, cooperates synergistically with PTEN as a tumor suppressor in multiple cancers. However, the underlying mechanism as to how CELF2 enhances PTEN activity remains unclear. Here, we report that CELF2 interacts with PREX2 and reduces the association of PREX2 with PTEN. Consistent with this observation, PTEN phosphatase activity is upregulated with CELF2 overexpression. In addition, overexpression of CELF2 represses both Akt phosphorylation and cell proliferation only in the presence of PTEN. In an ex vivo study, CELF2 gene delivery could significantly inhibit patient-derived xenografts (PDX) tumor growth. To further investigate the clinical relevance of this finding, we analyzed 87 paired clinical lung adenocarcinoma samples and the results showed that CELF2 protein expression is downregulated in tumor tissues and associated with poor prognosis. The CELF2 gene is located on the chromosome 10p arm, a region frequently lost in human cancers, including breast invasive carcinoma, low-grade glioma and glioblastoma. Analysis of TCGA datasets showed that CELF2 expression is also associated with shorter patient survival time in all these cancers. Overall, our work suggests that CELF2 plays a novel role in PI3-K signaling by antagonizing the oncogenic effect of PREX2.

scholarly journals Calcium-dependent growth regulation of small cell lung cancer cells by neuropeptides

2006 ◽  
Vol 13 (4) ◽  
pp. 1069-1084 ◽  
Author(s):  
Thomas Gudermann ◽  
Susanne Roelle
Keyword(s):  
Protein Kinase ◽  
Growth Regulation ◽  
Hormone Receptors ◽  
Apoptotic Cell ◽  
Small Cell Lung Carcinoma ◽  
Small Cell ◽  
Mitogen Activated Protein Kinase ◽  
Small Cell Lung ◽  
Cell Lung Carcinoma ◽  
Mitogenic Signal

Approximately 15–25% of all primary cancers of the lung are classified histologically as small cell lung carcinoma (SCLC), a subtype characterized by rapid growth and a poor prognosis. Neuropeptide hormones like bombesin/gastrin-releasing peptide, bradykinin or galanin are the principal mitogenic stimuli of this tumour entity. The mitogenic signal is transmitted into the cell via heptahelical neuropeptide hormone receptors, which couple to the heterotrimeric G proteins of the Gq/11 familiy. Subsequent activation of phospholipase Cβ (PLCβ) entails the activation of protein kinase C and the elevation of the intracellular calcium concentration. There is mounting evidence to support the notion that calcium mobilization is the key event that initiates different mitogen-activated protein kinase cascades. Neuropeptide-dependent proliferation of SCLC cells relies on parallel activation of the Gq/11/PLCβ/Ras/extracellular signal-regulated kinase and the c-jun N-terminal kinase pathways, while selective engagement of either signalling cascade alone results in growth arrest and differentiation or apoptotic cell death. Basic experimental research has the potential to identify and validate novel therapeutic targets located at critical points of convergence of different mitogenic signal transduction pathways. In the case of SCLC, targeting the distinct components of the Ca2+ influx pathway as well as critical Ca2+-dependent cellular effectors may be rewarding in this regard.

scholarly journals The Fusion Circular RNA F-circEA1 Promotes Non-small Cell Lung Carcinoma Progression through ALK Downstream Signaling

2021 ◽  
Author(s):  
yinping Huo ◽  
Tangfeng Lv ◽  
Mingxiang Ye ◽  
Suhua Zhu ◽  
Jiaxin Liu ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Lung Carcinoma ◽  
Small Cell Lung Carcinoma ◽  
Circular Rna ◽  
Small Cell ◽  
Rt Pcr ◽  
Transplanted Tumors ◽  
Small Cell Lung ◽  
Cell Lung Carcinoma ◽  
Downstream Signaling

Abstract Background Circular RNA has a stable closed structure, which plays an important role in the occurrence and development of tumors. However, there are no reports on the relationship between fusion circular RNA and EML4-ALK variant 1, or their underlying molecular mechanisms in non-small cell lung carcinoma (NSCLC). Methods To test F-circEA1 in NCI-H3122 cells (carrying the EML4-ALK variant 1 gene) by RT-PCR, FISH and Sanger sequencing; To determine cell proliferation with a CCK-8 assay. Transwell experiments were used to detect cell migration and invasion. Cell cycle stage and apoptosis were detected by flow cytometry. The sensitivity of cells to crizotinib was tested using a CCK-8 assay. RT-PCR and western blots were used to measure the expression of EML4-ALK1 and downstream signaling factors associated with ALK. Subcutaneously transplanted tumors were used in nude mice to determine the effect of F-circEA1 on tumor formation and the expression of EML4-ALK1 by immunohistochemistry. Statistical analyses were carried by GraphPad Prism 8.0 and differences between groups were compared using Student's t test. Difference with p value <0.05 is statistically significant.Results F-circEA1 was present both in the cytoplasm and nucleus of NCI-H3122 cells. F-circEA1 was contributed to cell proliferation, metastasis, invasion. F-circEA1 induced cell arrest, promoted cell apoptosis and improved drug sensitivity to crizotinib. After knockdown with F-circEA1, subcutaneously transplanted tumors in nude mice grew slowly, the expression of EML4-ALK1 in tumor tissues decreased significantly. The mRNA and protein levels of EML4-ALK1 decreased after knockdown of F-circEA1 but increased after its overexpression. The protein expression of downstream ALK signaling factors increased after overexpression of F-circEA1, but not at the mRNA level.Conclusions We have confirmed a potential carcinogenenic and therapeutic role for F-circEA1 in NSCLC. Our experimental results may provide a new biomarker, treatment method, and prognostic monitoring index for use in the clinic.

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