Abstract
Therapeutic targets for more effective and less toxic treatments of lung cancer remain important. Here we report the identification of the integral nuclear envelope protein TMEM209 as a critical driver of human lung cancer growth and survival. TMEM209 expression was normally limited to testis, but we found that it was widely expressed in lung cancer, in which it localized to the nuclear envelope, Golgi apparatus, and the cytoplasm of lung cancer cells. Ectopic overexpression of TMEM209 promoted cell growth, whereas TMEM209 attenuation was sufficient to block growth. Mass spectrometric analysis identified the nucleoporin protein NUP205 as a TMEM209-interacting protein, stabilizing NUP205 and increasing the level of c-Myc in the nucleus. Taken together, our findings indicate that TMEM209 overexpression and TMEM209-NUP205 interaction are critical drivers of lung cancer proliferation, suggesting a promising new target for lung cancer therapy.
Highlights
Lung cancer is one of the leading causes of death in the worldwide [1]
In addition to these cytotoxic drugs, several molecular targeted agents, such as monoclonal antibodies against VEGF or epidermal growth factor receptor (EGFR; i.e., cetuximab/anti-EGFR) as well as inhibitors for EGFR tyrosine kinase and anaplastic lymphoma kinase were developed and are applied in clinical practice [6, 7]
TMEM209 expression in lung cancers and normal tissues To identify novel target molecules for the development of therapeutic agents and/or diagnostic biomarkers of lung cancer, we had previously carried out gene expression profile analysis of 120 lung carcinomas using cDNA microarray containing 27,648 genes or expressed sequence tags [9,10,11,12,13,14]
Summary
Lung cancer is one of the leading causes of death in the worldwide [1]. Many genetic alterations associated with development and progression of lung cancers have been reported and contributed to the better understanding of the molecular mechanisms of pulmonary carcinogenesis [2]. Over the last few decades, several newly developed cytotoxic agents such as paclitaxel, docetaxel, gemcitabine, and vinorelbine have begun to offer multiple choices for treatment of patients with advanced lung cancer, but each of those regimens confers only a modest survival benefit compared with cisplatin-based therapies [3,4,5]. In addition to these cytotoxic drugs, several molecular targeted agents, such as monoclonal antibodies against VEGF (i.e., bevacizumab/anti-VEGF) or epidermal growth factor receptor (EGFR; i.e., cetuximab/anti-EGFR) as well as inhibitors for EGFR tyrosine kinase (i.e., gefitinib and erlotinib) and anaplastic lymphoma kinase (i.e., crizotinib) were developed and are applied in clinical practice [6, 7]. Targeting TMEM209 and/or TMEM209–NUP205 interaction could be a promising therapeutic strategy for lung cancer therapy
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