Medizinische Universität Graz - Research portal
Selected Publication:
SHR Neuro Cancer Cardio Lipid Metab Microb
Rao, S; Sigl, V; Wimmer, RA; Novatchkova, M; Jais, A; Wagner, G; Handschuh, S; Uribesalgo, I; Hagelkruys, A; Kozieradzki, I; Tortola, L; Nitsch, R; Cronin, SJ; Orthofer, M; Branstetter, D; Canon, J; Rossi, J; D'Arcangelo, M; Botling, J; Micke, P; Fleur, L; Edlund, K; Bergqvist, M; Ekman, S; Lendl, T; Popper, H; Takayanagi, H; Kenner, L; Hirsch, FR; Dougall, W; Penninger, JM.
RANK rewires energy homeostasis in lung cancer cells and drives primary lung cancer.
Genes Dev. 2017; 31(20):2099-2112
Doi: 10.1101/gad.304162.117
[OPEN ACCESS]
Web of Science
PubMed
FullText
FullText_MUG
- Co-authors Med Uni Graz
- Kenner Lukas
- Popper Helmuth
- Altmetrics:
- Dimensions Citations:
- Plum Analytics:
- Scite (citation analytics):
- Abstract:
- 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 KRas G12D in mouse lung epithelial cells markedly impairs the progression of KRas G12D -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 KRas G12D -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. © 2017 Rao et al.; Published by Cold Spring Harbor Laboratory Press.
- Find related publications in this database (using NLM MeSH Indexing)
- Alveolar Epithelial Cells - metabolism
- Animals -
- Cell Respiration -
- Cells, Cultured -
- Energy Metabolism -
- Female -
- Gonadal Steroid Hormones - physiology
- Homeostasis -
- Humans -
- Lung - metabolism
- Lung Neoplasms - drug therapy
- Lung Neoplasms - metabolism
- Male -
- Mice -
- Mitochondria - metabolism
- Neoplastic Stem Cells - metabolism
- Proto-Oncogene Proteins p21(ras) - genetics
- Receptor Activator of Nuclear Factor-kappa B - antagonists & inhibitors
- Receptor Activator of Nuclear Factor-kappa B - genetics
- Receptor Activator of Nuclear Factor-kappa B - metabolism
- Receptor Activator of Nuclear Factor-kappa B - physiology
- Respiratory Mucosa - metabolism
- Find related publications in this database (Keywords)
- RANK
- energy homeostasis
- lung cancer
- lung cancer stem-like cells