Mitotic Spindle Apparatus Abnormalities in Chronic Obstructive Pulmonary Disease Cells: A Potential Pathway to Lung Cancer

Abstract

Chronic obstructive pulmonary disease (COPD) is a longterm lung disease characterized by irreversible lung damage resulting in airflow limitation, abnormal permanent airspace enlargement, and emphysema. Cigarette smoking is the major cause of COPD with 15% to 30% of smokers developing either disease. About 50% to 80% of patients with lung cancer have preexisting COPD and smokers who have COPD are at an increased risk for developing lung cancer. Therefore, COPD is considered an independent risk for lung cancer, even after adjusting for smoking. A crucial early event in carcinogenesis is the induction of the genomic instability through alterations in the mitotic spindle apparatus. To date, the underlying mechanism by which COPD contributes to lung cancer risk is unclear. We hypothesized that tobacco smoke carcinogens induce mitotic spindle apparatus abnormalities and alter expression of crucial genes leading to increased genomic instability and ultimately tumorigenesis. To test our hypothesis, we assessed the genotoxic effects of a potent tobacco-smoke carcinogen [4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, (NNK)] on bronchial epithelial cells from patients with COPD and normal bronchial epithelial cells and identified genes associated with mitotic spindle defects and chromosome missegregation that also overlap with lung cancer. Our results indicate that exposure to NNK leads to a significantly altered spindle orientation, centrosome amplification, and chromosome misalignment in COPD cells as compared with normal epithelial cells. In addition, we identified several genes (such as AURKA, AURKB, and MAD2L2) that were upregulated and overlap with lung cancer suggesting a potential common pathway in the transition from COPD to lung cancer.

LINC00958 promotes bladder cancer carcinogenesis by targeting miR-490-3p and AURKA

“…It encodes a cell cycle-regulated kinase that participates in microtubule formation [ 27 , 28 ]. High-throughput data analysis demonstrated that AURKA was identified as a tumor promoter in all types of cancers [ 29 – 31 ]. Upregulation of AURKA has been reported in bladder cancer progression, which might be a potential therapeutic target for bladder cancer [ 32 – 34 ].…”

Cigarette smoke condensate induces centrosome clustering in normal lung epithelial cells

“…Beas‐2B and NSCLC cells were synchronized in mitosis using a double thymidine block as detailed in our previous study. 17 Briefly, cells were treated with 2.5 mM thymidine (Cat# T1895, Sigma–Aldrich) for 24 h, incubated in a medium without thymidine for 14 h, and incubated with 2.5 mM thymidine for another 24 h, all at 37°C. After washing cells with PBS, they were then allowed to grow for 72 h. The mitotic abnormalities (multipolar spindles) were examined and compared between CSC‐treated cells and untreated (control) cells.…”

“…With acquisition settings kept constant, Z‐stacks of images at 0.2‐mm intervals were acquired, and maximum intensity projections were created. 16 , 17 , 18 , 19 …”

Integrative metabolomics and transcriptomics analysis reveals novel therapeutic vulnerabilities in lung cancer

“…Cells were seeded at 5000 cells/well in 96‐well plates and grown for 24 h before treatment with various concentrations of AZD‐6482 and PI‐828 (Sigma‐Aldrich, # 1173900‐33‐8 and Tocris‐ 2814/1) for up to 48 h. Cell viability was assessed using the XTT assay. 29 Absorbance was read at 475 nm with a standard plate reader. The IC 50 values were calculated using GraphPad Prism software version 8.02 (GraphPad Prism, RRID:SCR_002798).…”