The mitochondrially-localized nucleoside diphosphate kinase D (NME4) is a novel metastasis suppressor
Marie‐Lise Lacombe, Frédéric Lamarche, Olivier De Wever, Teresita Padilla‐Benavides, Alyssa Carlson, Imran Khan, Anda Huna, Sophie Vacher, Claire Calmel, Céline Desbourdes, Cécile Cottet‐Rousselle, Isabelle Hininger‐Favier, Stéphane Attia, Béatrice Nawrocki‐Raby, Joël Raingeaud, Christelle Machon, Jérôme Guitton, Morgane Le Gall, Guilhem Clary, Cédric Broussard, Philippe Chafey, Patrice Thérond, David Bernard, Éric Fontaine, Małgorzata Tokarska-Schlattner, Patricia S. Steeg, Ivan Bièche, Uwe Schlattner, Mathieu Boissan
Abstract
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.