scholarly journals Elevating CDCA3 levels in non-small cell lung cancer enhances sensitivity to platinum-based chemotherapy

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Katrina Kildey ◽  
Neha S. Gandhi ◽  
Katherine B. Sahin ◽  
Esha T. Shah ◽  
Eric Boittier ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Genome Instability ◽  
Small Cell ◽  
Small Cell Lung ◽  
Protein Levels ◽  
Platinum Based Chemotherapy ◽  
Platinum Agents

AbstractPlatinum-based chemotherapy remains the cornerstone of treatment for most non-small cell lung cancer (NSCLC) cases either as maintenance therapy or in combination with immunotherapy. However, resistance remains a primary issue. Our findings point to the possibility of exploiting levels of cell division cycle associated protein-3 (CDCA3) to improve response of NSCLC tumours to therapy. We demonstrate that in patients and in vitro analyses, CDCA3 levels correlate with measures of genome instability and platinum sensitivity, whereby CDCA3high tumours are sensitive to cisplatin and carboplatin. In NSCLC, CDCA3 protein levels are regulated by the ubiquitin ligase APC/C and cofactor Cdh1. Here, we identified that the degradation of CDCA3 is modulated by activity of casein kinase 2 (CK2) which promotes an interaction between CDCA3 and Cdh1. Supporting this, pharmacological inhibition of CK2 with CX-4945 disrupts CDCA3 degradation, elevating CDCA3 levels and increasing sensitivity to platinum agents. We propose that combining CK2 inhibitors with platinum-based chemotherapy could enhance platinum efficacy in CDCA3low NSCLC tumours and benefit patients.

scholarly journals GOLPH3 Overexpression is Closely Correlated with Poor Prognosis in Human Non-Small Cell Lung Cancer and Mediates its Metastasis Through Upregulating MMP-2 and MMP-9

2015 ◽  
Vol 35 (3) ◽  
pp. 969-982 ◽  
Author(s):  
Ran Wang ◽  
Zun-fu Ke ◽  
Fen Wang ◽  
Wen-hui Zhang ◽  
Yue-feng Wang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Clinical Stage ◽  
Small Cell ◽  
Migration And Invasion ◽  
Small Cell Lung ◽  
Protein Levels ◽  
T Classification

Background/Aims: Golgi phosphoprotein 3 (GOLPH3) is a newly reported oncogene that plays a significant role in regulating cell growth. Recent research has shown that overexpression of GOLPH3 is correlated with patient survival and M classification in breast cancer and other cancers. However, the mechanisms by which GOLPH3 contributes to metastasis in non-small cell lung cancer (NSCLC) have not been previously clarified and are therefore the focus of this work. Methods: Immunohistochemistry (IHC) and western blotting analysis were performed to assess the GOLPH3 protein level, small interfering RNA (siRNA) and transwell assays were conducted to investigate the role of GOLPH3 in migration and invasion, and real-time PCR was performed to estimate the level of GOLPH3 mRNA expression. Results: GOLPH3 was significantly correlated with clinicopathological variables, such as the clinical stage (P=0.012), T classification (P=0.002) and metastasis (M classification) (P=0.008), in NSCLC patients and was negatively correlated with the prognosis. Knockdown of GOLPH3 significantly suppressed the migratory and invasive ability of NSCLC cell lines and downregulated the enzyme activity and protein levels of MMP-2 and MMP-9. Conclusions: The expression level of GOLPH3 is correlated with metastasis and prognosis in NSCLC, and GOLPH3 mediates metastasis by regulating the protein levels of MMP-2 and MMP-9 in vitro.

scholarly journals Diethylstilbestrol, a Novel ANO1 Inhibitor, Exerts an Anticancer Effect on Non-Small Cell Lung Cancer via Inhibition of ANO1

2021 ◽  
Vol 22 (13) ◽  
pp. 7100
Author(s):  
Yohan Seo ◽  
Sung Baek Jeong ◽  
Joo Han Woo ◽  
Oh-Bin Kwon ◽  
Sion Lee ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
High Throughput Screening ◽  
Fluorescent Protein ◽  
Yellow Fluorescent Protein ◽  
Small Cell ◽  
Channel Activity ◽  
Small Cell Lung ◽  
Protein Levels

Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-related mortality; thus, therapeutic targets continue to be developed. Anoctamin1 (ANO1), a novel drug target considered for the treatment of NSCLC, is a Ca2+-activated chloride channel (CaCC) overexpressed in various carcinomas. It plays an important role in the development of cancer; however, the role of ANO1 in NSCLC is unclear. In this study, diethylstilbestrol (DES) was identified as a selective ANO1 inhibitor using high-throughput screening. We found that DES inhibited yellow fluorescent protein (YFP) fluorescence reduction caused by ANO1 activation but did not inhibit cystic fibrosis transmembrane conductance regulator channel activity or P2Y activation-related cytosolic Ca2+ levels. Additionally, electrophysiological analyses showed that DES significantly reduced ANO1 channel activity, but it more potently reduced ANO1 protein levels. DES also inhibited the viability and migration of PC9 cells via the reduction in ANO1, phospho-ERK1/2, and phospho-EGFR levels. Moreover, DES induced apoptosis by increasing caspase-3 activity and PARP-1 cleavage in PC9 cells, but it did not affect the viability of hepatocytes. These results suggest that ANO1 is a crucial target in the treatment of NSCLC, and DES may be developed as a potential anti-NSCLC therapeutic agent.

Investigation of in vitro Activities of Cu2ZnSnS4 Nanoparticles in Human Non-Small Cell Lung Cancer

2021 ◽  
pp. 102304
Author(s):  
Suleyman Gokhan Colak ◽  
Canan Vejselova Sezer ◽  
Ruken Esra Demirdogen ◽  
Mine Ince ◽  
Fatih Mehmet Emen ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Small Cell Lung

scholarly journals Polymorphisms in the Gene Encoding Caspase 8 May Predict the Response to First-Line Platinum-Based Chemotherapy in Locally Advanced or Advanced Non-Small-Cell Lung Cancer

2021 ◽  
Vol 10 (5) ◽  
pp. 1126
Author(s):  
Michał Szczyrek ◽  
Radosław Mlak ◽  
Aneta Szudy-Szczyrek ◽  
Karolina Kędziora ◽  
Teresa Małecka-Massalska ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Locally Advanced ◽  
Distant Metastases ◽  
Small Cell ◽  
Caspase 8 ◽  
Small Cell Lung ◽  
Gene Encoding ◽  
Platinum Based Chemotherapy

Caspase 8 is a protein involved in the process of cell apoptosis, which may affect the efficacy of anti-cancer treatment. The aim of our study was to determine the impact of polymorphisms in the CASP-8 gene encoding caspase 8 on the prognosis in non-small-cell lung cancer (NSCLC). The study involved 99 patients with newly diagnosed locally advanced or metastatic NSCLC treated with platinum-based chemotherapy. The presence of the GG genotype was associated with distant metastases, smoking, and a family history of cancer. The higher risk of early progression was associated with weight loss and the CASP-8 genotype (GG vs. AG or AA: 20.51% vs. 2.86%). The higher risk of progression-free survival (PFS) shortening was associated with a higher stage of disease (hazard ratio (HR) = 2.50, 95% CI: 1.61–3.89, p < 0.0001), distant metastases (HR = 2.30, 95% CI: 1.42–3.72, p = 0.0016), and the GG genotype (HR = 1.68, 95% CI: 1.10–2.57, p = 0.0152). The influence of the GG genotype on the PFS was confirmed in a multivariate analysis (HR = 1.80, 95% CI: 1.06–3.05, p = 0.0317). We did not confirm the influence of CASP-8 genotypes on the overall survival (OS).

scholarly journals Mimicking Tumor Hypoxia in Non-Small Cell Lung Cancer Employing Three-Dimensional In Vitro Models

Cells ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 141
Author(s):  
Iwona Ziółkowska-Suchanek
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Tumor Hypoxia ◽  
Three Dimensional ◽  
In Vitro Models ◽  
Small Cell ◽  
Small Cell Lung ◽  
Multicellular Tumor Spheroid

Hypoxia is the most common microenvironment feature of lung cancer tumors, which affects cancer progression, metastasis and metabolism. Oxygen induces both proteomic and genomic changes within tumor cells, which cause many alternations in the tumor microenvironment (TME). This review defines current knowledge in the field of tumor hypoxia in non-small cell lung cancer (NSCLC), including biology, biomarkers, in vitro and in vivo studies and also hypoxia imaging and detection. While classic two-dimensional (2D) in vitro research models reveal some hypoxia dependent manifestations, three-dimensional (3D) cell culture models more accurately replicate the hypoxic TME. In this study, a systematic review of the current NSCLC 3D models that have been able to mimic the hypoxic TME is presented. The multicellular tumor spheroid, organoids, scaffolds, microfluidic devices and 3D bioprinting currently being utilized in NSCLC hypoxia studies are reviewed. Additionally, the utilization of 3D in vitro models for exploring biological and therapeutic parameters in the future is described.

scholarly journals Tumour-derived exosomal lncRNA-SOX2OT promotes bone metastasis of non-small cell lung cancer by targeting the miRNA-194-5p/RAC1 signalling axis in osteoclasts

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Jianjiao Ni ◽  
Xiaofei Zhang ◽  
Juan Li ◽  
Zhiqin Zheng ◽  
Junhua Zhang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Bone Metastasis ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Osteoclast Differentiation ◽  
Small Cell ◽  
Signalling Pathway ◽  
Small Cell Lung

AbstractBone is a frequent metastatic site of non-small cell lung cancer (NSCLC), and bone metastasis (BoM) presents significant challenges for patient survival and quality of life. Osteolytic BoM is characterised by aberrant differentiation and malfunction of osteoclasts through modulation of the TGF-β/pTHrP/RANKL signalling pathway, but its upstream regulatory mechanism is unclear. In this study, we found that lncRNA-SOX2OT was highly accumulated in exosomes derived from the peripheral blood of NSCLC patients with BoM and that patients with higher expression of exosomal lncRNA-SOX2OT had significantly shorter overall survival. Additionally, exosomal lncRNA-SOX2OT derived from NSCLC cells promoted cell invasion and migration in vitro, as well as BoM in vivo. Mechanistically, we discovered that NSCLC cell-derived exosomal lncRNA-SOX2OT modulated osteoclast differentiation and stimulated BoM by targeting the miRNA-194-5p/RAC1 signalling axis and TGF-β/pTHrP/RANKL signalling pathway in osteoclasts. In conclusion, exosomal lncRNA-SOX2OT plays a crucial role in promoting BoM and may serve as a promising prognostic biomarker and treatment target in metastatic NSCLC.

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