Glycogen synthase kinase 3 protein kinase activity is frequently elevated in human non-small cell lung carcinoma and supports tumour cell proliferation.

BACKGROUND: Glycogen synthase kinase 3 (GSK3) is a central regulator of cellular metabolism, development and growth. GSK3 activity was thought to oppose tumourigenesis, yet recent studies indicate that it may support tumour growth in some cancer types including in non-small cell lung carcinoma (NSCLC). We examined the undefined role of GSK3 protein kinase activity in tissue from human NSCLC. METHODS: The expression and protein kinase activity of GSK3 was determined in 29 fresh frozen samples of human NSCLC and patient-matched normal lung tissue by quantitative immunoassay and western blotting for the phosphorylation of three distinct GSK3 substrates in situ (glycogen synthase, RelA and CRMP-2). The proliferation and sensitivity to the small-molecule GSK3 inhibitor; CHIR99021, of NSCLC cell lines (Hcc193, H1975, PC9 and A549) and non-neoplastic type II pneumocytes was further assessed in adherent culture. RESULTS: Expression and protein kinase activity of GSK3 was elevated in 41% of human NSCLC samples when compared to patient-matched control tissue. Phosphorylation of GSK3α/ß at the inhibitory S21/9 residue was a poor biomarker for activity in tumour samples. The GSK3 inhibitor, CHIR99021 dose-dependently reduced the proliferation of three NSCLC cell lines yet was ineffective against type II pneumocytes. CONCLUSION: NSCLC tumours with elevated GSK3 protein kinase activity may have evolved dependence on the kinase for sustained growth. Our results provide further important rationale for exploring the use of GSK3 inhibitors in treating NSCLC.

Overexpression of the TXNDC5 protein in non-small cell lung carcinoma.

UNLABELLED: Thioredoxin domain containing protein 5 (TXNDC5) is a member of the thioredoxin (Trx) domain-containing family of proteins that have been implicated in cancer progression. The expression of TXNDC5 in non-small cell lung carcinoma (NSCLC) tumours compared to patient-matched normal lung tissue was determined and cell line models were used to determine if expression was regulated by hypoxia. PATIENTS AND METHODS: Samples of tumour and normal lung tissue were taken during surgery and immediately frozen. The expression of TXNDC5 was determined by Western blotting and immunohistochemistry. To analyse the effect of hypoxia on TXNDC5 expression NSCLC cell lines were used. RESULTS: Tumours from 18/29 (62%) individuals exhibited an increase in TXNDC5 expression compared to normal lung tissue (p<0.05). TXNDC5 expression was not elevated by hypoxia. CONCLUSION: TXNDC5 is up-regulated in the majority of resected human NSCLC. Cell line data indicates that the expression of TXNDC5 in tumour cells is not regulated by hypoxia.

Long-term follow-up of ultraflex metallic stents in benign and malignant central airway obstruction.

BACKGROUND: We report experience with Ultraflex metallic stents (Boston Scientific, Natick, MA) inserted at rigid bronchoscopy under general anesthesia for palliation of benign and malignant upper airway obstruction. METHODS: Notes of all patients treated with Ultraflex stents from 1999 to 2003 were reviewed for symptomatic response, spirometric data, and any complications before discharge home. Long-term outcome was assessed by questionnaires sent to patients' general practitioners. RESULTS: Recruited were 66 patients (12 benign, 54 malignant airway obstructions). Before discharge home, breathlessness improved in 11 of 12 patients with benign obstruction and in 39 of 54 with malignancies. Postoperative complications in 10 patients with malignant obstructions and in 2 patients with benign obstruction were successfully controlled. It was not possible to perform preoperative pulmonary function tests in most of the patients who presented as emergencies. Mean improvement in forced expiratory volume in 1 second was 0.88 liters in 3 patients with benign obstruction and 0.28 liters in 14 patients with malignant obstruction, and mean peak expiratory flow rate improved by 109 L/min and 97 L/min, respectively. General practitioners completed questionnaires for 12 benign patients and 46 of 54 patients with malignancies. At a mean follow-up of 1017 days (range, 46 to 1120 days), 10 of the 12 patients with benign disease were alive and 7 of 46 patients with malignant airway obstruction were alive, with a median survival of 128 days (mean, 361; range, 3 to 1859 days). Most survivors had Medical Research Council grade III breathlessness or better, with few stent-related symptoms. CONCLUSIONS: Ultraflex stents proved safe and effective in prolonged palliation of benign and malignant airways obstruction.