STK33-dependent transcriptional regulation of SFTA3 induces Cisplatin-resistance in lung adenocarcinoma

2019 ◽  
Vol 19 ◽  
Author(s):  
Kuilong Zhou ◽  
Runzhi Dong ◽  
Zhiheng Wang ◽  
Zhian Tang ◽  
Xuezhen Gao ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Transcriptional Regulation ◽  
Lung Adenocarcinoma ◽  
Cisplatin Resistance ◽  
Serine Threonine Kinase ◽  
Lung Cancer Patients ◽  
Threonine Kinase ◽  
Signaling Axis

: Drug-resistance has become a major obstacle for Cisplatin usage in non-small cell lung cancer. In this study, we identified a poorly-studied kinase Serine/Threonine Kinase 33 (STK33) as the most up-regulated kinase encoding gene in Cisplatin resistant lung adenocarcinoma. Additionally, STK33-dependent Cisplatin-resistance promotes tumor growth of lung adenocarcinoma both in vitro and in vivo. Clinically, STK33 expression was enriched in lung adenocarcinoma and was correlated to poor prognosis of lung cancer patients. Mechanically, STK33 promoted cell growth and Cisplatin-resistance of lung adenocarcinoma via transcriptional regulation of surfactant associated 3 (SFTA3), indicating that STK33-SFTA3 signaling axis could be a potential therapeutic target for Cisplatin-resistant lung adenocarcinoma.

HOXA4-Dependent Transcriptional Activation of AXL Promotes Cisplatin- Resistance in Lung Adenocarcinoma Cells

2019 ◽  
Vol 18 (14) ◽  
pp. 2062-2067 ◽  
Author(s):  
Shuo Yu ◽  
Hui Ren ◽  
Yang Li ◽  
Xuan Liang ◽  
Qian Ning ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Transcriptional Regulation ◽  
Lung Adenocarcinoma ◽  
Poor Prognosis ◽  
Cisplatin Resistance ◽  
Adenocarcinoma Cells ◽  
Lung Adenocarcinoma Cells ◽  
Encoding Gene

Background: Lung cancer is one of the most leading causes of cancer-related deaths in adults worldwide. Non-Small Cell Lung Cancer (NSCLC), which comprises 80 to 85% of all lung cancers, is the most lethal subtype of lung cancer with a 5-year survival of less than 13%. In this study, we identified a poorly-studied kinase PDK4 as the most up-regulated kinase encoding gene in Cisplatin resistant lung adenocarcinoma. Methods: In vitro cell viability assay and in vivo tumor xenograft assay were used in the detection of cell proliferation. RNA isolation, quantitative Real-Time PCR, Western blot analysis, immunohistochemistry were used to investigate the expression of RNA and protein. Lentivirus infection was used to regulate gene expression. Luciferase assays were used to monitor EPAS1 promoter activity. Results: In vivo PDK4 expression was elevated in a Cisplatin-resistant population of lung adenocarcinoma cells, PDK4-dependent Cisplatin-resistance promotes tumor growth of lung adenocarcinoma in vivo and in vitro, clinically PDK4 expression was associated with poor prognosis in lung adenocarcinoma patients, mechanically PDK4 promoted cell growth and Cisplatin-resistance of lung adenocarcinoma via transcriptional regulation of endothelial PAS domain-containing protein 1 (EPAS1). Conclusion: PDK4 is the most up-regulated kinase encoding gene in Cisplatin resistant lung adenocarcinoma and PDK4-dependent Cisplatin-resistance promotes tumor growth of lung adenocarcinoma mainly through transcriptional regulation of EPAS1. Enriched PDK4 expression was correlated with the poor prognosis of lung cancer patients, indicating that PDK4 could be a potential therapeutic target for Cisplatin-resistant lung adenocarcinoma.

scholarly journals USP9X-mediated KDM4C deubiquitination promotes lung cancer radioresistance by epigenetically inducing TGF-β2 transcription

2021 ◽  
Author(s):  
Xiaohua Jie ◽  
William Pat Fong ◽  
Rui Zhou ◽  
Ye Zhao ◽  
Yingchao Zhao ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Affinity Purification ◽  
Smad Signaling ◽  
Lung Cancer Patients ◽  
Lysine Specific Demethylase ◽  
Underlying Mechanisms ◽  
H3k9me3 Level ◽  
Critical Binding

AbstractRadioresistance is regarded as the main barrier to effective radiotherapy in lung cancer. However, the underlying mechanisms of radioresistance remain elusive. Here, we show that lysine-specific demethylase 4C (KDM4C) is overexpressed and correlated with poor prognosis in lung cancer patients. We provide evidence that genetical or pharmacological inhibition of KDM4C impairs tumorigenesis and radioresistance in lung cancer in vitro and in vivo. Moreover, we uncover that KDM4C upregulates TGF-β2 expression by directly reducing H3K9me3 level at the TGF-β2 promoter and then activates Smad/ATM/Chk2 signaling to confer radioresistance in lung cancer. Using tandem affinity purification technology, we further identify deubiquitinase USP9X as a critical binding partner that deubiquitinates and stabilizes KDM4C. More importantly, depletion of USP9X impairs TGF-β2/Smad signaling and radioresistance by destabilizing KDM4C in lung cancer cells. Thus, our findings demonstrate that USP9X-mediated KDM4C deubiquitination activates TGF-β2/Smad signaling to promote radioresistance, suggesting that targeting KDM4C may be a promising radiosensitization strategy in the treatment of lung cancer.

scholarly journals Arsenic sulfide reverses cisplatin resistance in non‐small cell lung cancer in vitro and in vivo through targeting PD‐L1

2021 ◽  
Vol 12 (19) ◽  
pp. 2551-2563
Author(s):  
Wei Tian ◽  
Yinping Sun ◽  
Yuping Cheng ◽  
Xiao Ma ◽  
Weina Du ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Cisplatin Resistance ◽  
Small Cell ◽  
Arsenic Sulfide ◽  
Small Cell Lung

scholarly journals WNK4 Kinase: from structure to physiology

2021 ◽  
Author(s):  
Adrian Rafael Murillo-de-Ozores ◽  
Alejandro Rodriguez-Gama ◽  
Hector Carbajal-Contreras ◽  
Gerardo Gamba ◽  
Maria Castaneda-Bueno
Keyword(s):  
Oxidative Stress ◽  
Mouse Models ◽  
Serine Threonine Kinase ◽  
Gene Encoding ◽  
Threonine Kinase ◽  
Physiological Conditions ◽  
Different Levels ◽  
Familial Hyperkalemic Hypertension

With No Lysine (K) kinase 4 (WNK4) belongs to a serine-threonine kinase family characterized by the atypical positioning of its catalytic lysine. Despite the fact that WNK4 has been found in many tissues, the majority of its study has revolved around its function in the kidney, specifically as a positive regulator of the thiazide-sensitive NaCl cotransporter (NCC) in the distal convoluted tubule (DCT) of the nephron. This is explained by the description of gain-of-function mutations in the gene encoding WNK4 that cause Familial Hyperkalemic Hypertension (FHHt). This disease is mainly driven by increased downstream activation of the Ste20-related Proline Alanine Rich Kinase (SPAK)/Oxidative Stress Responsive Kinase 1 (OSR1)-NCC pathway, which increases salt reabsorption in the DCT and indirectly impairs renal K+ secretion. Here, we review the large volume of information that has accumulated about different aspects of WNK4 function. We first review the knowledge on WNK4 structure and enumerate the functional domains and motifs that have been characterized. Then, we discuss WNK4 physiological functions based on the information obtained from in vitro studies and from a diverse set of genetically modified mouse models with altered WNK4 function. We then review in vitro and in vivo evidence on the different levels of regulation of WNK4. Finally, we go through the evidence that has suggested how different physiological conditions act through WNK4 to modulate NCC activity.

Effect of Octreotide on Neuroenolase Levels in Patients with Small Cell Lung Cancer

1994 ◽  
Vol 80 (5) ◽  
pp. 332-334 ◽  
Author(s):  
Enzo Soresi ◽  
Giovanni Invernizzi ◽  
Roberto Boffi ◽  
Umberto Borghini ◽  
Gianfranco Schiraldi ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Serum Levels ◽  
Small Cell ◽  
Small Cell Lung ◽  
Lung Cancer Patients ◽  
Octreotide Treatment

Aims and Background The somatostatin analog octreotide has an antiproliferative effect on small cell lung cancer lines in vitro and in experimental xenograft transplantation systems in vivo. Thus it is worth investigating octreotide activity in the clinical setting. Methods We studied the effect of octreotide (200 μg three times a day subcutaneously for seven days) on serum levels of the tumor marker neuroenolase in 13 patients with small cell lung cancer. Results A decrease in neuroenolase levels was observed at day 7 during octreotide treatment, with a mean ± SD of 32.6 ± 42.0 ng/ml compared to basal values of 44.4 ± 57.7 ng/ml and to washout values of 50.3 ± 65.7 ng/ml ( P < 0.03). Conclusions Our results indicate that octreotide is effective in reducing neuroenolase levels in small cell lung cancer patients. These data suggest a possible role for octreotide in the treatment of this kind of tumor.

scholarly journals Protein Serine/Threonine Kinase StkP Positively Controls Virulence and Competence in Streptococcus pneumoniae

2004 ◽  
Vol 72 (4) ◽  
pp. 2434-2437 ◽  
Author(s):  
Jose Echenique ◽  
Aras Kadioglu ◽  
Susana Romao ◽  
Peter W. Andrew ◽  
Marie-Claude Trombe
Keyword(s):  
Streptococcus Pneumoniae ◽  
Lung Infection ◽  
Signaling Network ◽  
Serine Threonine Kinase ◽  
Positive Regulation ◽  
Threonine Kinase

ABSTRACT In the Streptococcus pneumoniae genome, stkP, encoding a membrane-associated serine/threonine kinase, is not redundant (L. Novakova, S. Romao, J. Echenique, P. Branny, and M.-C. Trombe, unpublished results). The data presented here demonstrate that StkP belongs to the signaling network involved in competence triggering in vitro and lung infection and bloodstream invasion in vivo. In competence, functional StkP is required for activation of comCDE upstream of the autoregulated ring orchestrated by the competence-stimulating peptide. This is the first description of positive regulation of comCDE transcription in balance with its repression by CiaRH.

scholarly journals High Level of Staufen1 Expression Confers Longer Recurrence Free Survival to Non-Small Cell Lung Cancer Patients by Promoting THBS1 mRNA Degradation

2021 ◽  
Vol 23 (1) ◽  
pp. 215
Author(s):  
Florence Bonnet-Magnaval ◽  
Leïla Halidou Diallo ◽  
Valérie Brunchault ◽  
Nathalie Laugero ◽  
Florent Morfoisse ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Adhesion ◽  
Cancer Patients ◽  
Cancer Progression ◽  
Rna Binding ◽  
Recurrence Free Survival ◽  
Free Survival ◽  
Lung Cancer Patients

Stau1 is a pluripotent RNA-binding protein that is responsible for the post-transcriptional regulation of a multitude of transcripts. Here, we observed that lung cancer patients with a high Stau1 expression have a longer recurrence free survival. Strikingly, Stau1 did not impair cell proliferation in vitro, but rather cell migration and cell adhesion. In vivo, Stau1 depletion favored tumor progression and metastases development. In addition, Stau1 depletion strongly impaired vessel maturation. Among a panel of candidate genes, we specifically identified the mRNA encoding the cell adhesion molecule Thrombospondin 1 (THBS1) as a new target for Staufen-mediated mRNA decay. Altogether, our results suggest that regulation of THBS1 expression by Stau1 may be a key process involved in lung cancer progression.

scholarly journals Regulation of Yeast Actin Cytoskeleton-Regulatory Complex Pan1p/Sla1p/End3p by Serine/Threonine Kinase Prk1p

2001 ◽  
Vol 12 (12) ◽  
pp. 3759-3772 ◽  
Author(s):  
Guisheng Zeng ◽  
Xianwen Yu ◽  
Mingjie Cai
Keyword(s):  
Actin Cytoskeleton ◽  
Regulatory Protein ◽  
Strong Support ◽  
Stable Complex ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Cytoskeleton Organization ◽  
Actin Cytoskeleton Organization

The serine/threonine kinase Prk1p is known to be involved in the regulation of the actin cytoskeleton organization in budding yeast. One possible function of Prk1p is the negative regulation of Pan1p, an actin patch regulatory protein that forms a complex in vivo with at least two other proteins, Sla1p and End3p. In this report, we identified Sla1p as another substrate for Prk1p. The phosphorylation of Sla1p by Prk1p was established in vitro with the use of immunoprecipitated Prk1p and in vivo with the use ofPRK1 overexpression, and was further supported by the finding that immunoprecipitated Sla1p contained PRK1- and ARK1-dependent kinase activities. Stable complex formation between Prk1p and Sla1p/Pan1p in vivo could be observed once the phosphorylation reaction was blocked by mutation in the catalytic site of Prk1p. Elevation of Prk1p activities in wild-type cells resulted in a number of deficiencies, including those in colocalization of Pan1p and Sla1p, endocytosis, and cell wall morphogenesis, likely attributable to a disintegration of the Pan1p/Sla1p/End3p complex. These results lend a strong support to the model that the phosphorylation of the Pan1p/Sla1p/End3p complex by Prk1p is one of the important mechanisms by which the organization and functions of the actin cytoskeleton are regulated.

Discovery of a novel linc01125 isoform in serum exosomes as a promising biomarker for NSCLC diagnosis and survival assessment

2021 ◽  
Author(s):  
Jianfeng Xian ◽  
Yuyuan Zeng ◽  
Shizhen Chen ◽  
Liming Lu ◽  
Li Liu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Area Under The Curve ◽  
Lung Cancer Patients ◽  
Non Invasive ◽  
Invasive Method ◽  
Highly Correlated ◽  
Nsclc Patients ◽  
Serum Exosomes

Abstract A non-invasive method to distinguish potential lung cancer patients would improve lung cancer prevention. We employed the RNA-Seq analysis to profile serum exosomal long non-coding RNAs (lncRNAs) from non-small cell lung cancer (NSCLC) patients and pneumonia controls, and then determined the diagnostic and prognostic value of a promising lncRNA in four datasets. We identified 90 dysregulated lncRNAs for NSCLC and found the most significant lncRNA was a novel isoform of linc01125. Serum exosomal linc01125 could distinguish NSCLC cases from disease-free and tuberculosis controls, with the area under the curve (AUC) values as 0.662 (95% confidence interval [CI]= 0.614-0.711) and 0.624 (95%CI= 0.522–0.725), respectively. High expression of exosomal linc01125 was also correlated with an unfavorable overall survival of NSCLC (hazard ratio [HR] = 1.58, 95%CI = 1.01–2.49). Clinic treatment decreased serum exosomal linc01125 in NSCLC patients (P = 0.036). Linc01125 functions to inhibit cancer growth and metastasis via acting as a competing endogenous RNA to up-regulate TNFAIP3 expression by sponging miR-19b-3p. Notably, the oncogenic transformation of 16HBE leads to decreased linc01125 in cells but increased linc01125 in cell-derived exosomes. The expression of linc01125 in total exosomes was highly correlated with that in tumor-associated exosomes in serum. Moreover, lung cancer cells were capable of releasing linc01125 into exosomes in vitro and in vivo. Our analyses suggest serum exosomal linc01125 as a promising biomarker for non-invasively diagnosing NSCLC and predicting the prognosis of NSCLC.

scholarly journals Inhibition of Bcr serine kinase by tyrosine phosphorylation.

1996 ◽  
Vol 16 (3) ◽  
pp. 998-1005 ◽  
Author(s):  
J Liu ◽  
Y Wu ◽  
G Z Ma ◽  
D Lu ◽  
L Haataja ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Tyrosine Phosphorylation ◽  
Kinase Activity ◽  
Philadelphia Chromosome ◽  
Wild Type ◽  
Serine Kinase ◽  
Serine Threonine Kinase ◽  
Threonine Kinase

The first exon of the BCR gene encodes a new serine/threonine protein kinase. Abnormal fusion of the BCR and ABL genes, resulting from the formation of the Philadelphia chromosome (Ph), is the hallmark of Ph-positive leukemia. We have previously demonstrated that the Bcr protein is tyrosine phosphorylated within first-exon sequences by the Bcr-Abl oncoprotein. Here we report that in addition to tyrose 177 (Y-177), Y-360 and Y283 are phosphorylated in Bcr-Abl proteins in vitro. Moreover, Bcr tyrosine 360 is phosphorylated in vivo within both Bcr-Abl and Bcr. Bcr mutant Y177F had a greatly reduced ability to transphosphorylate casein and histone H1, whereas Bcr mutants Y177F and Y283F had wild-type activities. In contrast, the Y360F mutation had little effect on Bcr's autophosphorylation activity. Tyrosine-phosphorylated Bcr, phosphorylated in vitro by Bcr-Abl, was greatly inhibited in its serine/threonine kinase activity, impairing both auto- and transkinase activities of Bcr. Similarly, the isolation of Bcr from cells expressing Bcr-Abl under conditions that preserve phosphotyrosine residues also reduced Bcr's kinase activity. These results indicate that tyrosine 360 of Bcr is critical for the transphosphorylation activity of Bcr and that in Ph-positive leukemia, Bcr serine/threonine kinase activity is seriously impaired.

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