TP53 Induced Glycolysis and Apoptosis Regulator and Monocarboxylate Transporter 4 drive metabolic reprogramming with c-MYC and NFkB activation in breast cancer.
TP53 induced glycolysis and apoptosis regulator
c-MYC
glycolysis
metabolic heterogeneity
mitochondrial metabolism
monocarboxylate transporter 4
Journal
International journal of cancer
ISSN: 1097-0215
Titre abrégé: Int J Cancer
Pays: United States
ID NLM: 0042124
Informations de publication
Date de publication:
01 11 2023
01 11 2023
Historique:
revised:
22
06
2023
received:
20
12
2022
accepted:
29
06
2023
medline:
8
9
2023
pubmed:
27
7
2023
entrez:
27
7
2023
Statut:
ppublish
Résumé
Breast cancer is composed of metabolically coupled cellular compartments with upregulation of TP53 Induced Glycolysis and Apoptosis Regulator (TIGAR) in carcinoma cells and loss of caveolin 1 (CAV1) with upregulation of monocarboxylate transporter 4 (MCT4) in fibroblasts. The mechanisms that drive metabolic coupling are poorly characterized. The effects of TIGAR on fibroblast CAV1 and MCT4 expression and breast cancer aggressiveness was studied using coculture and conditioned media systems and in-vivo. Also, the role of cytokines in promoting tumor metabolic coupling via MCT4 on cancer aggressiveness was studied. TIGAR downregulation in breast carcinoma cells reduces tumor growth. TIGAR overexpression in carcinoma cells drives MCT4 expression and NFkB activation in fibroblasts. IL6 and TGFB drive TIGAR upregulation in carcinoma cells, reduce CAV1 and increase MCT4 expression in fibroblasts. Tumor growth is abrogated in the presence of MCT4 knockout fibroblasts and environment. We discovered coregulation of c-MYC and TIGAR in carcinoma cells driven by lactate. Metabolic coupling primes the tumor microenvironment allowing for production, uptake and utilization of lactate. In sum, aggressive breast cancer is dependent on metabolic coupling.
Substances chimiques
Apoptosis Regulatory Proteins
0
Lactic Acid
33X04XA5AT
NF-kappa B
0
TP53 protein, human
0
Tumor Suppressor Protein p53
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1671-1683Subventions
Organisme : NCI NIH HHS
ID : K08 CA175193
Pays : United States
Organisme : NCI NIH HHS
ID : R37 CA234239
Pays : United States
Organisme : NIAMS NIH HHS
ID : T32 AR052273
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA056036
Pays : United States
Informations de copyright
© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.
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