期刊
BMC BIOLOGY
卷 19, 期 1, 页码 -出版社
BMC
DOI: 10.1186/s12915-021-01155-5
关键词
Mitochondrial dynamics; Invasion; Metastasis; Nucleoside diphosphate kinase; NME4; Metabolic reprogramming; Prognosis biomarker; Retrograde signaling
类别
资金
- Fondation pour la Recherche Medicale (FRM) [DPM20121125557]
- CMIRA Explo'ra doc fellowship of the Region Rhone Alpes
- French National Research Agency [ANR-15-IDEX-02]
- Institut Universitaire de France
- Groupement des Entreprises Francaises contre le Cancer (GEFLUC)
- Canceropole-Ile de France [2015-1-EMERG-25-INSERM 6-1]
- Institut National contre le Cancer [INCA 2015-1-PL BIO-01]
- Wesleyan University
The study reveals that mitochondrial nucleoside diphosphate kinase plays a suppressive role in metastatic cancer by promoting mitochondrial alterations leading to metastasis. Results suggest that NME4 expression could serve as a favorable prognostic indicator for cancer patients.
Background Mitochondrial nucleoside diphosphate kinase (NDPK-D, NME4, NM23-H4) is a multifunctional enzyme mainly localized in the intermembrane space, bound to the inner membrane. Results We constructed loss-of-function mutants of NDPK-D, lacking either NDP kinase activity or membrane interaction and expressed mutants or wild-type protein in cancer cells. In a complementary approach, we performed depletion of NDPK-D by RNA interference. Both loss-of-function mutations and NDPK-D depletion promoted epithelial-mesenchymal transition and increased migratory and invasive potential. Immunocompromised mice developed more metastases when injected with cells expressing mutant NDPK-D as compared to wild-type. This metastatic reprogramming is a consequence of mitochondrial alterations, including fragmentation and loss of mitochondria, a metabolic switch from respiration to glycolysis, increased ROS generation, and further metabolic changes in mitochondria, all of which can trigger pro-metastatic protein expression and signaling cascades. In human cancer, NME4 expression is negatively associated with markers of epithelial-mesenchymal transition and tumor aggressiveness and a good prognosis factor for beneficial clinical outcome. Conclusions These data demonstrate NME4 as a novel metastasis suppressor gene, the first localizing to mitochondria, pointing to a role of mitochondria in metastatic dissemination.
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