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  • Metabolic reprogramming of normal oral fibroblasts correlated with increased glycolytic metabolism of oral squamous cell carcinoma and precedes their activation into carcinoma associated fibroblasts.

Metabolic reprogramming of normal oral fibroblasts correlated with increased glycolytic metabolism of oral squamous cell carcinoma and precedes their activation into carcinoma associated fibroblasts.

Cellular and molecular life sciences : CMLS (2019-07-05)
Zhuoyuan Zhang, Zhenjie Gao, Saroj Rajthala, Dipak Sapkota, Harsh Dongre, Himalaya Parajuli, Salwa Suliman, Ridhima Das, Longjiang Li, Laurence A Bindoff, Daniela Elena Costea, Xiao Liang
ABSTRACT

Cancers show a metabolic shift towards aerobic glycolysis. By "corrupting" their microenvironment, carcinoma cells are able to obtain energy substrates to "fuel" their mitochondrial metabolism and cell growth in an autophagy-associated, paracrine manner. However, the metabolic changes and role of normal fibroblasts in this process remain unclear. We devised a novel, indirect co-culture system to elucidate the mechanisms of metabolic coupling between stromal cells and oral squamous cell carcinoma (OSCC) cells. Here, we showed that normal oral fibroblasts (NOFs) and OSCC become metabolically coupled through several processes before acquiring an activated phenotype and without inducing senescence. We observed, for the first time, that NOFs export mitochondria towards OSCCs through both direct contact and via indirect mechanisms. NOFs are activated and are able to acquire a cancer-associated fibroblasts metabolic phenotype when co-cultivation with OSSC cells, by undergoing aerobic glycolysis, secreting more reactive oxygen species (ROS), high L-lactate and overexpressing lactate exporter MCT-4, leading to mitochondrial permeability transition pore (mPTP) opening, hypoxia, and mitophagy. On the other hand, Cav-1-low NOFs generate L-lactate to "fuel" mitochondrial metabolism and anabolic growth of OSCC. Most interestingly, the decrease in AMPK activity and PGC-1α expression might involve in regulation of ROS that functions to maintain final energy and metabolic homeostasis. This indicated, for the first time, the existence of ATP and ROS homeostasis during carcinogenesis. Our study suggests that an efficient therapeutical approach has to target the multiple mechanisms used by them to corrupt the normal surrounding stroma and metabolic homeostasis.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
2′,7′-Dichlorofluorescin diacetate, ≥97%
Sigma-Aldrich
Dulbecco′s Modified Eagle′s Medium/Nutrient Mixture F-12 Ham, With L-glutamine, 15 mM HEPES, and sodium bicarbonate, liquid, sterile-filtered, suitable for cell culture
Sigma-Aldrich
Tetramethylrhodamine ethyl ester perchlorate, suitable for fluorescence, ≥90% (HPCE)
Sigma-Aldrich
Trypsin-EDTA solution, 1 ×, sterile; sterile-filtered, BioReagent, suitable for cell culture, 0.5 g porcine trypsin and 0.2 g EDTA • 4Na per liter of Hanks′ Balanced Salt Solution with phenol red
Sigma-Aldrich
Hydrocortisone, BioReagent, suitable for cell culture
Sigma-Aldrich
(+)-Sodium L-ascorbate, crystalline, ≥98%
Sigma-Aldrich
Carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone, ≥98% (TLC), powder