Autonomous glucose metabolic reprogramming of tumour cells under hypoxia: opportunities for targeted therapy
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(2020) 39:185
REVIEW
Open Access
Autonomous glucose metabolic reprogramming of tumour cells under hypoxia: opportunities for targeted therapy Mingyao Huang†, Liang Yang†, Xueqiang Peng†, Shibo Wei, Qing Fan, Shuo Yang, Xinyu Li, Bowen Li, Hongyuan Jin, Bo Wu, Jingang Liu and Hangyu Li*
Abstract Molecular oxygen (O2) is a universal electron acceptor that is eventually synthesized into ATP in the mitochondrial respiratory chain of all metazoans. Therefore, hypoxia biology has become an organizational principle of cell evolution, metabolism and pathology. Hypoxia-inducible factor (HIF) mediates tumour cells to produce a series of glucose metabolism adaptations including the regulation of glucose catabolism, glycogen metabolism and the biological oxidation of glucose to hypoxia. Since HIF can regulate the energy metabolism of cancer cells and promote the survival of cancer cells, targeting HIF or HIF mediated metabolic enzymes may become one of the potential treatment methods for cancer. In this review, we summarize the established and recently discovered autonomous molecular mechanisms that can induce cell reprogramming of hypoxic glucose metabolism in tumors and explore opportunities for targeted therapy. Keywords: Hypoxia, Tumour, Glucose, Metabolic reprogramming
Background Hypoxia is a characteristic feature of locally advanced solid tumours resulting from an imbalance in oxygen (O2) supply and consumption in the proximity [1]. The disordered vasculature that is developed in response to the oxygen demand of rapidly growing tumours leads to widespread hypoxic regions in solid tumours. In cancer, hypoxia is associated with tumour progression and poor prognosis. Sustained hypoxia in growing tumours may lead to clinically aggressive phenotypes, increased invasive capacity, tumour cell metastasis, and resistance to both chemotherapy and radiation treatment [2, 3]. Oxygen tension in normal human tissues usually exceeds 40 mmHg; in contrast, oxygen tension in tumours may * Correspondence: [email protected] † Mingyao Huang, Liang Yang and Xueqiang Peng contributed equally to this work. Department of General Surgery, the Fourth Affiliated Hospital, China Medical University, Shenyang 110032, China
persist at 0–20 mmHg [4]. In normal cells, hypoxia usually induces growth arrest and causes death. However, under hypoxic conditions, tumour cells can adapt to poor nutrition and unfavourable microenvironments through genomic changes, thereby remaining vital [1]. In addition, cancer stem cells (CSC) are particularly responsible for hyper-adaptation to unfavorable TME. Indeed, CSC plays an important role in tumorigenesis and invasion/metastasis potential. Importantly, metabolic reprogramming is essential for maintaining the selfrenewal of CSC [5, 6]. Studies also found that, as the tumour volume increases, the depletion of glucose will lead to the cytolysis and necrosis of tumour cells [7]. These suggests that metabolism may play an important role in tumorigenesis and development. There are ten hallmarks including genome i
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