Hypoxia-reprogrammed tricarboxylic acid cycle promotes the growth of human breast tumorigenic cells

Abstract

Clinical applications of antiangiogenic agents profoundly affect tumor cell behaviors via the resultant hypoxia. To date, how the hypoxia regulates tumor cells remains unclear. Here, we show that hypoxia promotes the growth of human breast tumorigenic cells that repopulate tumors [tumor-repopulating cells (TRCs)] in vitro and in vivo. This stimulating effect is ascribed to hypoxia-induced reactive oxygen species (ROS) that activates Akt and NF-κB, dependent on the attenuated tricarboxylic acid (TCA) cycle. We find that fumarate is accumulated in the TCA cycle of hypoxic TRCs, leading to glutathione succination, NADPH/NADP + decrease, and an increase in ROS levels. Mechanistically, hypoxia-increased HIF-1α transcriptionally downregulates the expression of mitochondrial phosphoenolpyruvate carboxykinase (PCK2), leading to TCA cycle attenuation and fumarate accumulation. These findings reveal that hypoxia-reprogrammed TCA cycle promotes human breast TRCs growth via a HIF-1α-downregulated PCK2 pathway, implying a need for a combination of an antiangiogenic therapy with an antioxidant modulator.

Green chicory leaf extract exerts anti-inflammatory effects through suppressing LPS-induced MAPK/NF-κB activation and hepatoprotective activity in vitro

“…Previously, CLE was examined as a tremendous source of polyphenol (Sahan et al, 2017;Sinkovič et al, 2015) and though we found a high content of gallic acid among 11 standards and Our study highly recommended to characterize the bioactive compounds in the green chicory leaf. Phenolic compounds that mostly found in plants are play roles in the prevention of oxidative damage in living organisms that perpetuated an enormous amount of chronic diseases (Graziani et al, 2005;Mijan et al, 2019;Tang et al, 2019). Furthermore, reactive oxygen species (ROS) are inevitable byproducts in physiological processes that required neutralized by antioxidants and enzymes.…”

Identification of Hub Genes Associated With Hepatocellular Carcinoma Using Robust Rank Aggregation Combined With Weighted Gene Co-expression Network Analysis

“…Upon suppression of autophagy, levels of glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK, a protein encoded by PCK2) are reduced in the human HCC cell line HepG2 ( Jeon et al, 2015 ). Hypoxia-inducible factor 1α (HIF-1α) can promote the growth of human breast tumor-repopulating cells by downregulating PCK2 ( Tang et al, 2019 ). However, a number of studies have reported that PEPCK coordinates the regulation of central carbon metabolism to promote tumor cell growth ( Montal et al, 2015 ).…”

Role of hypoxia inducible factor-1 in cancer stem cells (Review)

“…The α-KG analogue dimethyl 2-ketoglutarate allows excess succinate/fumarate to be transferred from the mitochondria to the cytoplasm, where it can impair prolyl hydroxylase and thus stabilize and activate HIF-1α, eventually leading to increased glycolysis and the acquisition of the stem-like characteristics of breast cancer cells (118). In addition, the upregulation of HIF-1α, under hypoxia, inhibits the expression of mitochondrial phosphoenolpyruvate carboxykinase, which leads to a weakened tricarboxylic acid cycle and the enrichment of fumarate, ultimately leading to increased ROS levels and breast CSC growth (123). In conclusion, HIF-1 appears to mainly act as an intermediate participant regulating the complex conversion mechanism of glycolysis and OXPHOS and the generation and maintenance of stemness in CSCs.…”