RANK rewires energy homeostasis in lung cancer cells and drives primary lung cancer.
نویسندگان
چکیده
Lung cancer is the leading cause of cancer deaths. Besides smoking, epidemiological studies have linked female sex hormones to lung cancer in women; however, the underlying mechanisms remain unclear. Here we report that the receptor activator of nuclear factor-kB (RANK), the key regulator of osteoclastogenesis, is frequently expressed in primary lung tumors, an active RANK pathway correlates with decreased survival, and pharmacologic RANK inhibition reduces tumor growth in patient-derived lung cancer xenografts. Clonal genetic inactivation of KRasG12D in mouse lung epithelial cells markedly impairs the progression of KRasG12D -driven lung cancer, resulting in a significant survival advantage. Mechanistically, RANK rewires energy homeostasis in human and murine lung cancer cells and promotes expansion of lung cancer stem-like cells, which is blocked by inhibiting mitochondrial respiration. Our data also indicate survival differences in KRasG12D -driven lung cancer between male and female mice, and we show that female sex hormones can promote lung cancer progression via the RANK pathway. These data uncover a direct role for RANK in lung cancer and may explain why female sex hormones accelerate lung cancer development. Inhibition of RANK using the approved drug denosumab may be a therapeutic drug candidate for primary lung cancer.
منابع مشابه
The role and mechanisms of zinc oxide nanoparticles in the improvement of the radiosensitivity of lung cancer cells in clinically relevant megavoltage radiation energies in-vitro
Objective(s): Semiconductor zinc oxide nanoparticles (ZnO NPs) have unique properties, such as inherent selectivity and photosensitization effects under ultraviolet (UV) radiation. ZnO NPs serve as promising anticancer agents. However, UV radiation limits their penetration into the body. In most clinical settings, it is essential to use high-energy photons in the treatment of deep-seated tumors...
متن کاملRadiosensitization effect of ZnO nanoparticles in lung cancer cells at clinically relevant megavoltage energy
Introduction: Radiation therapy is one of the major modalities that have long been used in cancer treatment. Radiotherapy is often accompanied by early and late toxicity and side effects and narrow therapeutic window. Similarity in radiation absorption properties of tumors and neighboring healthy tissues is often the reason for low specificity of radiation therapy. Development ...
متن کاملIdentification of a Novel Tumor-Binding Peptide for Lung Cancer Through in-vitro Panning
Tumor-targeted therapies are playing growing roles in cancer research. The exploitation of these powerful therapeutic modalities largely depends on the discovery of tumor-targeting ligands. Phage display has proven a promising high throughput screening tool for the identification of novel specific peptides with high binding affinity to cancer cells. In the present study, we describe the use of ...
متن کاملIdentification of a Novel Tumor-Binding Peptide for Lung Cancer Through in-vitro Panning
Tumor-targeted therapies are playing growing roles in cancer research. The exploitation of these powerful therapeutic modalities largely depends on the discovery of tumor-targeting ligands. Phage display has proven a promising high throughput screening tool for the identification of novel specific peptides with high binding affinity to cancer cells. In the present study, we describe the use of ...
متن کاملBioinformatics Identification of miRNA-mRNA Regulatory Network Contributing Primary Lung Cancer
Introduction: In clinical practice, distinguishing invasive lung tumors from primary tumors remains a challenge. With recent advances in understanding biological alterations of tumorigenesis and molecular analytic technologies, using these molecular alterations can be sensitive and tumor-specific as biomarker for the stratification of patients. In this study, the molecular network of miRNA-mRNA...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید
ثبت ناماگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید
ورودعنوان ژورنال:
- Genes & development
دوره 31 20 شماره
صفحات -
تاریخ انتشار 2017