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Emerging roles of hypoxia-inducible factors and reactive oxygen species in cancer and pluripotent stem cells

Significance Statement

Multicelluar organisms require oxygen homeostasis to maintain proper cellular metabolisms and bioenergetics. However, organisms that tolerate oxygen availability, especially to hypoxia, face the harsh environmental circumstances during their lives. In contrast to an expected strong suppression of protein synthesis, a large number of animals present increased levels of antioxidant defenses during oxygen deprivation. These observations have puzzled us for more than 20 years. Two predominant theories seemed to be irreconcilable: (1) hypoxia would decrease reactive oxygen species (ROS) production (long period), (2) the induction of antioxidant enzymes by hypoxia would require the overproduction of ROS (early period). This induction of antioxidant enzymes during hypoxia was viewed as a way to prepare animals for oxidative damage that may happen ultimately during re-oxygenation. This is a preparation stage for oxidative stress, which idea appeared in 1998.

(stem cell niches). Reactive oxygen species (ROS) have long been recognized as toxic by-products of aerobic metabolism that are harmful to living cells, leading to DNA damage, senescence, or cell death. hypoxia-inducible factors may promote a cancer stem cell state, whereas the loss of hypoxia-inducible factors induces the production of cellular ROS and activation of proteins p53 and p16Ink4a, which lead to tumor cell death and senescence. Thus, reduced ROS seems to inhibit hypoxia-inducible factors regulation in cancer cells of commit the cell reprogramming of stem cells. However, at the late stage of stress, increased ROS performs the inverted function.

However, many cases of increased oxidative damage in several hypoxia-tolerant organisms under hypoxia. Moreover, over the year, the first idea of assured decrease in ROS under hypoxia was challenged. Instead, recent findings indicate that the production of ROS actually increases in response to hypoxia. Hypoxia increase the generation of ROS, which prevents hydroxylation of hypoxia-inducible factors proteins by inducing their transcription as negative feedback. Moreover, the hypoxic conditions enhance the generation of induced pluripotent stem cells (iPSCs). During reprogramming of somatic cells into a pluripotent stem cell state, cells attain a metabolic state typically observed in embryonic stem cells (ESCs). ESCs and iPSCs share similar bioenergetic metabolisms, including decreased mitochondrial number and activity, and induced anaerobic glycolysis. Thus, extent of transition of hypoxia to anoxia might regulate the level of ROS which controlled the converse effects for hypoxia-inducible factors dependent regulation.

This review discusses the current knowledge regarding the emerging roles of ROS homeostasis in cellular reprogramming and the implications of hypoxic regulation in cancer development, especially at the long exposure of hypoxia stage. Moreover, the current understanding of emerging insights into the intricate roles and functions of hypoxia-inducible factors and ROS in tumor growth, apoptosis and senescence, and their roles in reprogramming cells into pluripotent stem cells via repression of tumor suppressor genes. Several crucial roles of the hypoxia-inducible factors -signaling in the regulation of stem cell self-renewal and its pluripotency are clarified in this review.

Emerging roles of hypoxia inducible factors and reactive oxygen species in cancer and pluripotent stem cells. Global Medical Discovery

 

Journal Reference

Kaohsiung J Med Sci. 2015;31(6):279-86.

Saito S1, Lin YC2, Tsai MH3, Lin CS3, Murayama Y4, Sato R5, Yokoyama KK6.

Show Affiliations
  1. Saito Laboratory of Cell Technology, Yaita, Tochigi, Japan.
  2. School of Dentistry, College of Dental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
  3. Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
  4. College of Engineering, Nihon University, Koriyama, Fukushima, Japan.
  5. SPK Co., Ltd., Aizuwakamatsu, Fukushima, Japan.
  6. Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. Electronic address: [email protected]

Abstract

Eukaryotic organisms require oxygen homeostasis to maintain proper cellular function for survival. During conditions of low oxygen tension (hypoxia),cells activate the transcription of genes that induce an adaptive response, which supplies oxygen to tissues. Hypoxia and hypoxia-inducible factors (HIFs) may contribute to the maintenance of putative cancer stem cells, which can continue self-renewal indefinitely and express stemness genes in hypoxic stress environments (stem cell niches).  Reactive  oxygen  species (ROS) have long been recognized as toxic by-products of aerobic metabolism that are harmful to living cells, leading to DNA damage, senescence, or cell death. hypoxia-inducible factors may promote a cancer stem cell state, whereas the loss of hypoxia-inducible factors induces the production of cellular ROS and activation of proteins p53 and p16(Ink4a), which lead to tumor cell death and senescence. ROS seem to inhibit hypoxia-inducible factors regulation in cancer cells. By contrast, controversial data have suggested that hypoxia increases the generation of ROS, which prevents hydroxylation of hypoxia-inducible factors proteins by inducing their transcription as negative feedback. Moreover, hypoxic conditions enhance the generation of induced pluripotent stem cells (iPSCs). During reprogramming of somatic cells into a PSC state, cells attain a metabolic state typically observed in embryonic stem cells (ESCs). ESCs and iPSCs share similar bioenergetic metabolisms, including decreased mitochondrial number and activity, and induced anaerobic glycolysis. This review discusses the current knowledge regarding the emerging roles of ROS homeostasis in cellular reprogramming and the implications of hypoxic regulation in cancer development.

Copyright © 2015. Published by Elsevier Taiwan.

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About The Author

Dr. Kazunari K. Yokoyama completed his Ph.D. at University of Tokyo, Department of Science, Division of Biophysics and Biochemistry at 1979. He was as a post-doctoral fellow in Albert Einstein College of Medicine, New York, USA and Beckman Research Institute of City of Hope, Duarte, CA, USA, and then became an assistant professor of the same department of Beckman Research Institute of City of Hope in USA. In 1985, he returned to RIKEN Institute, Tsukuba Life Science Center, Japan and in 1990 became a head of Gene Engineering Division, Gene Bank in RIKEN. During this period, he went to Pasteur Institute, Paris Cedex, France, as the exchange scholar on 1991. Now he is a professor of Kaohsiung medical University in Taiwan (from 2009 to the present). He has published more than 250 papers included Nature, Science, Nature Genetics, Molecular Cell, Genes & Development, Nature Structural Biological Chemistry, EMBO J and Proc Natl Acad Sci USA and a serving as peer reviewer of Japanese International Awards of Sciences, Japan Awards and member of American Association for Cancer Research, American Society for Microbiology and International Stem Cell Research and so on.