title: Targeting stromal-induced pyruvate kinase M2 nuclear translocation impairs oxphos and prostate cancer metastatic spread.
abstract: Cancer associated fibroblasts (CAFs) are key determinants of cancer progression. In prostate carcinoma (PCa), CAFs induce epithelial-mesenchymal transition (EMT) and metabolic reprogramming of PCa cells towards oxidative phosphorylation (OXPHOS), promoting tumor growth and metastatic dissemination. We herein establish a novel role for pyruvate kinase M2 (PKM2), an established effector of Warburg-like glycolytic behavior, in OXPHOS metabolism induced by CAFs. Indeed, CAFs promote PKM2 post-translational modifications, such as cysteine oxidation and Src-dependent tyrosine phosphorylation, allowing nuclear migration of PKM2 and the formation of a trimeric complex with hypoxia inducible factor-1α (HIF-1α) and the transcriptional repressor Differentially Expressed in Chondrocytes-1 (DEC1). DEC1 recruitment is mandatory for downregulating miR205 expression, thereby fostering EMT execution and metabolic switch toward OXPHOS. Furthermore, the analysis of a cohort of PCa patients reveals a significant positive correlation between PKM2 nuclear localization and cancer aggressiveness, thereby validating our in vitro observations. Crucially, in vitro and in vivo pharmacological targeting of PKM2 nuclear translocation using DASA-58, as well as metformin, impairs metastatic dissemination of PCa cells in SCID mice. Our study indicates that impairing the metabolic tumor:stroma interplay by targeting the PKM2/OXPHOS axis, may be a valuable novel therapeutic approach in aggressive prostate carcinoma.
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50134, Florence, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Giannoni
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50134, Florence, Italy.
authors.forename: Maria Letizia
authors.initials: ML
authors.lastname: Taddei
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50134, Florence, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Morandi
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50134, Florence, Italy.
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Comito
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50134, Florence, Italy.
authors.forename: Maura
authors.initials: M
authors.lastname: Calvani
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50134, Florence, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Bianchini
authors.affiliation: Department of Chemistry, University of Florence, 50019, Sesto Fiorentino, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Richichi
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50134, Florence, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Raugei
authors.affiliation: Division of Nephrology, Department of Medicine, McMaster University, L8N4A6, Hamilton, Ontario, Canada.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Wong
authors.affiliation: Division of Nephrology, Department of Medicine, McMaster University, L8N4A6, Hamilton, Ontario, Canada.
authors.forename: Damu
authors.initials: D
authors.lastname: Tang
authors.affiliation: Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50134, Florence, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Chiarugi
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D001665:Binding Sites; D002277:Carcinoma / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D015331:Cohort Studies; D003545:Cysteine / Q000737:chemistry; D005347:Fibroblasts / Q000378:metabolism; D005947:Glucose / Q000737:chemistry; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007150:Immunohistochemistry; D019344:Lactic Acid / Q000737:chemistry; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D008687:Metformin / Q000737:chemistry; D051379:Mice; D016513:Mice, SCID; D035683:MicroRNAs / Q000378:metabolism; D009362:Neoplasm Metastasis; D010084:Oxidation-Reduction; D010085:Oxidative Phosphorylation; D010100:Oxygen / Q000737:chemistry; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D011770:Pyruvate Kinase / Q000378:metabolism*; D013963:Thyroid Hormones / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D000097810:Thyroid Hormone-Binding Proteins
chemical_list: D002352:Carrier Proteins; D003545:Cysteine; D005947:Glucose; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019344:Lactic Acid; D008565:Membrane Proteins; D008687:Metformin; D035683:MicroRNAs; D010100:Oxygen; D011770:Pyruvate Kinase; D013963:Thyroid Hormones; D025521:Tumor Suppressor Proteins; D000097810:Thyroid Hormone-Binding Proteins; C403671:DELEC1 protein, human; C497442:HIF1A protein, human; C534425:MIR205, human
keywords: cancer associated fibroblasts; epithelial-mesenchymal transition; hypoxia inducible factor-1α; prostate cancer; pyruvate kinase M2