title: Reciprocal metabolic reprogramming through lactate shuttle coordinately influences tumor-stroma interplay.
abstract: Cancer-associated fibroblasts (CAF) engage in tumor progression by promoting the ability of cancer cells to undergo epithelial-mesenchymal transition (EMT), and also by enhancing stem cells traits and metastatic dissemination. Here we show that the reciprocal interplay between CAFs and prostate cancer cells goes beyond the engagement of EMT to include mutual metabolic reprogramming. Gene expression analysis of CAFs cultured ex vivo or human prostate fibroblasts obtained from benign prostate hyperplasia revealed that CAFs undergo Warburg metabolism and mitochondrial oxidative stress. This metabolic reprogramming toward a Warburg phenotype occurred as a result of contact with prostate cancer cells. Intercellular contact activated the stromal fibroblasts, triggering increased expression of glucose transporter GLUT1, lactate production, and extrusion of lactate by de novo expressed monocarboxylate transporter-4 (MCT4). Conversely, prostate cancer cells, upon contact with CAFs, were reprogrammed toward aerobic metabolism, with a decrease in GLUT1 expression and an increase in lactate upload via the lactate transporter MCT1. Metabolic reprogramming of both stromal and cancer cells was under strict control of the hypoxia-inducible factor 1 (HIF1), which drove redox- and SIRT3-dependent stabilization of HIF1 in normoxic conditions. Prostate cancer cells gradually became independent of glucose consumption, while developing a dependence on lactate upload to drive anabolic pathways and thereby cell growth. In agreement, pharmacologic inhibition of MCT1-mediated lactate upload dramatically affected prostate cancer cell survival and tumor outgrowth. Hence, cancer cells allocate Warburg metabolism to their corrupted CAFs, exploiting their byproducts to grow in a low glucose environment, symbiotically adapting with stromal cells to glucose availability.
authors: Department of Biochemical Sciences, Tuscany Tumor Institute and Center for Research, Transfer and High Education DenoTHE, University of Florence, Florence, Italy.
authors: Tania
authors: T
authors: Fiaschi
authors: Alberto
authors: A
authors: Marini
authors: Elisa
authors: E
authors: Giannoni
authors: Maria Letizia
authors: ML
authors: Taddei
authors: Paolo
authors: P
authors: Gandellini
authors: Alina
authors: A
authors: De Donatis
authors: Michele
authors: M
authors: Lanciotti
authors: Sergio
authors: S
authors: Serni
authors: Paolo
authors: P
authors: Cirri
authors: Paola
authors: P
authors: Chiarugi
mesh_terms: D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D005947:Glucose / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000378:metabolism; D006019:Glycolysis; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D027501:Monocarboxylic Acid Transporters / Q000235:genetics / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D056566:Sirtuin 3 / Q000235:genetics / Q000378:metabolism; D014183:Transplantation, Heterologous
chemical_list: D051272:Glucose Transporter Type 1; D051793:Hypoxia-Inducible Factor 1; D027501:Monocarboxylic Acid Transporters; D009124:Muscle Proteins; C406962:SLC16A4 protein, human; C495677:SLC2A1 protein, human; D019344:Lactic Acid; C466093:SIRT3 protein, human; D056566:Sirtuin 3; D005947:Glucose