Cancer Letters

Cancer Letters

Volume 356, Issue 2, Part A, 28 January 2015, Pages 263-267
Cancer Letters

Mini-review
Hypoxia and hypoxia inducible factors in tumor metabolism

https://doi.org/10.1016/j.canlet.2014.01.032 Get rights and content

Abstract

Because of the abnormal vasculature, most growing solid tumors contain regions that experience either acute or chronic hypoxia. However, tumor cells can maintain a high glycolytic rate even when there is enough oxygen supply. Hypoxia-inducible factors (HIFs) play crucial role in the response of tumor cells to this distinct microenvironment by shifting energy production from mitochondria towards glycolysis. In this review, we focus on the metabolism of tumor cell survival in hypoxic microenvironments. Furthermore, we also emphasize the mechanisms by which hypoxia and HIFs regulate tumor metabolism.

Introduction

One of the most validated explanations for altered metabolism in tumors is the poorly formed tumor vasculature that exists within tumors [1]. Because of the rapid growth of tumor cells, significant regions of the tumors are located at a great distance from the supporting blood vessels [2]. The growth of tumor cells is typically limited to a region of approximately 10 cells of a blood vessel, which results in the formation of an oxygen and nutrient gradient that supplies the tumor [3]. Generally, tumor cells respond to these specific conditions and adjust their metabolism to adapt to this unusual microenvironment [4].

Important factors in the response of tumor cells to this distinct microenvironment are the activities of the hypoxia inducible factors (HIFs). The HIFs are essential for the maintenance of cellular oxygen homeostasis and hypoxia adaptation when oxygen levels are too low for the cell [5], [6]. HIFs are associated with the PAS (Per-ARNT-Sim) family of basic helix-loop-helix transcription factors that bind as heterodimers to DNA. HIFs are composed of an oxygen-dependent α subunit and an oxygen-independent β subunit. The α subunit has three isoforms: HIF-1α, HIF-2α, and HIF-3α. The β subunit, which is also known as aryl hydrocarbon receptor nuclear translocator (ARNT), has only two isoforms HIF-1β and HIF-2β. The α-subunit is transported into the nucleus and dimerizes with the β subunit when oxygen concentrations is below 6% [7], [8], [9]. This complex binds to the core sequence 5-RCGTG-3 of hypoxia responsive element (HRE) within the enhancer promoter region of HIF target genes. HREs facilitate the transcription of target genes, which results in adaptation of tumors to the hypoxic state, including angiogenesis, anaerobic energy supply, metabolic regulation, pH balance, and cell apoptosis [10], [11], [12], [13].

Section snippets

Characteristics of tumor metabolism

The citric acid cycle (or Krebs cycle) occurs in the mitochondrial matrix, a crucial components metabolic pathway, where most of the aerobic organisms generate chemical energy in the form of adenosine triphosphate (ATP), which is derived from the catabolism of glucose, fats, and proteins into CO2. This cycle also supplies precursors for the synthesis of some amino acids and reduces nicotinamide adenine dinucleotide (NAD+) to NADH for specific biochemical reactions [14], [15].

Cellular metabolism

The effects of HIF regulation on glucose metabolism in cancer cells

Cellular metabolism within solid tumors is known to be significantly different from normal tissue [20]. In normal tissue, approximately 10% of the cell’s energy is generated by glycolysis, whereas mitochondrial aerobic respiration accounts for the other 90%. However, in tumor tissues, more than 50% of cellular energy is generated by glycolysis and the other parts are produced in mitochondria [2]. Interestingly, this switch is maintained even when there is enough O2 present to maintain

The effects of HIF regulation in lipid metabolism in cancer cells

Although the Warburg effect has been recognized since the 1920s, little attention has been paid to lipid metabolism. In response to glucose and nutrition deprivation, fatty acids can also be consumed to provide energy for cancer cell survival. This process takes place through β-oxidation, in which peroxisomes consume molecular oxygen and cleave two carbon atoms per cycle to produce acetyl-CoA and bioenergy. It has been reported that the stimulation of fatty acid oxidation is enough to maintain

The effects of HIF regulation on DNA damage and repair in cancer cells

Tumor hypoxia has been linked to increase in rate of mutation, decrease DNA repair and results in genetic instability. Varying levels and lengths causes distinct effects on the cell cycle and on DNA repair to manage genetic mutation and tumor progression. Even when exposed to similar levels of O2, a short-term, acute hypoxic exposure can cause different biological consequences within tumors than a longer-term, chronic hypoxic exposure [39], [40], [41].

Exposure to cycling hypoxia results in high

The role of HIFs in tumor cell apoptosis

The contribution of HIF-1α in the regulation of hypoxic cell survival or death remains controversial. It has been reported that HIF-1α can have either pro-apoptotic or anti-apoptotic effects in different experimental systems [47]. During hypoxia, there is a delicate balance exists between the factors, which induce or prevent apoptosis or even activate proliferation. It has been suggested that cells undergo apoptotic or adjust to hypoxia and alive, depend on the severity of the hypoxia, because

The role of HIFs in radiotherapy and chemotherapy

Because of hypoxia, treating solid tumors are big hurdle for radiation therapy because tumors show resistance to most anticancer drugs [53], [54]. During severe or prolonged hypoxia, most of the cells undergo programmed cell death. However, some of them adjust to environments stress, survive by avoiding necrosis and apoptosis, and may cause aggressive phenotype, which suggest that cell non-sensitive to apoptosis in a tumor will be resistance to anticancer treatments [48], [55].

Major challenge

Conclusion

Hypoxia has been known as one of the basic hallmark of solid tumors. HIF-1 plays an important role in the cellular response to tumor hypoxia and imposes biggest hurdle in radiation therapy and chemotherapy [63], [64], [65], [66], [67], [68], [69]. HIF-1 is crucial in tumor angiogenesis, tumor invasion and metastasis. HIF-1 also controls the glucose, lipid, and amino acid metabolism in cancer cells. Further, hypoxia and the HIFs step in the metabolic crosstalk between cancer cells and their

Conflicts of Interest

The authors declare no conflict of interest.

Acknowledgements

We sincerely apologize to all colleagues whose original work could not be cited because of space limitations.

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    Co-corresponding author at: Mouse Cancer Genetics Program, Center for Cancer Research, National Institutes of Health, National Cancer Institute, Frederick, MD 21702, USA. Tel.: +1 301 846 7331.

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