Samuel E. J. Preston, Michael S. Dahabieh, Raúl Ernesto Flores González, Christophe Gonçalves, Vincent R. Richard, Matthew Leibovitch, Eleanor Dakin, Theodore Papadopoulos, Carolina Lopez Naranjo, Paige A. McCallum, Fan Huang, Natascha Gagnon, Stephanie Perrino, René P. Zahedi, Christoph H. Borchers, Russell G. Jones, Pnina Brodt, Wilson H. Miller Jr., Sonia V. del Rincón
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引用次数: 0
Abstract
Dysregulation of the mitogen-activated protein kinase interacting kinases 1/2 (MNK1/2)–eukaryotic initiation factor 4E (eIF4E) signaling axis promotes breast cancer progression. MNK1 is known to influence cancer stem cells (CSCs); self-renewing populations that support metastasis, recurrence, and chemotherapeutic resistance, making them a clinically relevant target. The precise function of MNK1 in regulating CSCs, however, remains unexplored. Here, we generated MNK1 knockout cancer cell lines, resulting in diminished CSC properties in vitro and slowed tumor growth in vivo. Using a multiomics approach, we functionally demonstrated that loss of MNK1 restricts tumor cell metabolic adaptation by reducing glycolysis and increasing dependence on oxidative phosphorylation. Furthermore, MNK1-null breast and pancreatic tumor cells demonstrated suppressed metastasis to the liver, but not the lung. Analysis of The Cancer Genome Atlas (TCGA) data from breast cancer patients validated the positive correlation between MNK1 and glycolytic enzyme protein expression. This study defines metabolic perturbations as a previously unknown consequence of targeting MNK1/2, which may be therapeutically exploited.
期刊介绍:
Science Advances, an open-access journal by AAAS, publishes impactful research in diverse scientific areas. It aims for fair, fast, and expert peer review, providing freely accessible research to readers. Led by distinguished scientists, the journal supports AAAS's mission by extending Science magazine's capacity to identify and promote significant advances. Evolving digital publishing technologies play a crucial role in advancing AAAS's global mission for science communication and benefitting humankind.