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Novel roles of folic acid as redox regulator: Modulation of reactive oxygen species sinker protein expression and maintenance of mitochondrial redox homeostasis on hepatocellular carcinoma.

Abstract We provide herein several lines of evidence to substantiate that folic acid (or folate) is a micronutrient capable of functioning as a novel redox regulator on hepatocellular carcinoma. First, we uncovered that folate deficiency could profoundly downregulate two prominent anti-apoptotic effectors including survivin and glucose-regulated protein-78. Silencing of either survivin or glucose-regulated protein-78 via small interfering RNA interfering technique established that both effectors could serve as reactive oxygen species sinker proteins. Second, folate deficiency-triggered oxidative-nitrosative stress could strongly induce endoplasmic reticulum stress that in turn could provoke cellular glutathione depletion through the modulation of the following two crucial events: (1) folate deficiency could strongly inhibit Bcl-2 expression leading to severe suppression of the mitochondrial glutathione pool and (2) folate deficiency could also profoundly inhibit two key enzymes that governing cellular glutathione redox regulation including γ-glutamylcysteinyl synthetase heavy chain, a catalytic enzyme for glutathione biosynthesis, and mitochondrial isocitrate dehydrogenase 2, an enzyme responsible for providing nicotinamide adenine dinucleotide phosphate necessary for regenerating oxidized glutathione disulfide back to glutathione via mitochondrial glutathione reductase. Collectively, we add to the literature new data to strengthen the notion that folate is an essential micronutrient that confers a novel role to combat reactive oxygen species insults and thus serves as a redox regulator via upregulating reactive oxygen species sinker proteins and averting mitochondrial glutathione depletion through proper maintenance of redox homeostasis via positively regulating glutathione biosynthesis, glutathione transporting system, and mitochondrial glutathione recycling process.
PMID
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Authors

Mayor MeshTerms
Keywords

Folic acid

hepatocellular carcinoma

mitochondrial isocitrate dehydrogenase

mitochondrial redox homeostasis

reactive oxygen species sinker proteins

redox regulator

Journal Title tumour biology : the journal of the international society for oncodevelopmental biology and medicine
Publication Year Start




PMID- 28639913
OWN - NLM
STAT- MEDLINE
DA  - 20170622
DCOM- 20170711
LR  - 20170713
IS  - 1423-0380 (Electronic)
IS  - 1010-4283 (Linking)
VI  - 39
IP  - 6
DP  - 2017 Jun
TI  - Novel roles of folic acid as redox regulator: Modulation of reactive oxygen
      species sinker protein expression and maintenance of mitochondrial redox
      homeostasis on hepatocellular carcinoma.
PG  - 1010428317702649
LID - 10.1177/1010428317702649 [doi]
AB  - We provide herein several lines of evidence to substantiate that folic acid (or
      folate) is a micronutrient capable of functioning as a novel redox regulator on
      hepatocellular carcinoma. First, we uncovered that folate deficiency could
      profoundly downregulate two prominent anti-apoptotic effectors including survivin
      and glucose-regulated protein-78. Silencing of either survivin or
      glucose-regulated protein-78 via small interfering RNA interfering technique
      established that both effectors could serve as reactive oxygen species sinker
      proteins. Second, folate deficiency-triggered oxidative-nitrosative stress could 
      strongly induce endoplasmic reticulum stress that in turn could provoke cellular 
      glutathione depletion through the modulation of the following two crucial events:
      (1) folate deficiency could strongly inhibit Bcl-2 expression leading to severe
      suppression of the mitochondrial glutathione pool and (2) folate deficiency could
      also profoundly inhibit two key enzymes that governing cellular glutathione redox
      regulation including gamma-glutamylcysteinyl synthetase heavy chain, a catalytic 
      enzyme for glutathione biosynthesis, and mitochondrial isocitrate dehydrogenase
      2, an enzyme responsible for providing nicotinamide adenine dinucleotide
      phosphate necessary for regenerating oxidized glutathione disulfide back to
      glutathione via mitochondrial glutathione reductase. Collectively, we add to the 
      literature new data to strengthen the notion that folate is an essential
      micronutrient that confers a novel role to combat reactive oxygen species insults
      and thus serves as a redox regulator via upregulating reactive oxygen species
      sinker proteins and averting mitochondrial glutathione depletion through proper
      maintenance of redox homeostasis via positively regulating glutathione
      biosynthesis, glutathione transporting system, and mitochondrial glutathione
      recycling process.
FAU - Lai, Kun-Goung
AU  - Lai KG
AD  - 1 Department of Radiation Oncology, Tungs' Taichung Metroharbor Hospital,
      Taichung, Taiwan.
FAU - Chen, Chi-Fen
AU  - Chen CF
AD  - 2 Clinical Laboratories, Yuan's General Hospital, Kaohsiung, Taiwan.
AD  - 3 Department of Medical Laboratory and Biotechnology Science, Kaohsiung Medical
      University, Kaohsiung, Taiwan.
AD  - 4 Shu-Zen Junior College of Medicine and Management, Kaohsiung, Taiwan.
FAU - Ho, Chun-Te
AU  - Ho CT
AD  - 5 Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical
      University, Taipei, Taiwan.
FAU - Liu, Jun-Jen
AU  - Liu JJ
AD  - 6 School of Medical Laboratory Science and Biotechnology, Taipei Medical
      University, Taipei, Taiwan.
FAU - Liu, Tsan-Zon
AU  - Liu TZ
AD  - 7 Translational Research Laboratory, Cancer Center, Taipei Medical University
      Hospital, Taipei, Taiwan.
FAU - Chern, Chi-Liang
AU  - Chern CL
AD  - 8 Department of Medical Laboratory Science and Biotechnology, Fooyin University, 
      Kaohsiung, Taiwan.
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Tumour Biol
JT  - Tumour biology : the journal of the International Society for Oncodevelopmental
      Biology and Medicine
JID - 8409922
RN  - 0 (BIRC5 protein, human)
RN  - 0 (Heat-Shock Proteins)
RN  - 0 (Inhibitor of Apoptosis Proteins)
RN  - 0 (Proto-Oncogene Proteins c-bcl-2)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (molecular chaperone GRP78)
RN  - 935E97BOY8 (Folic Acid)
RN  - EC 1.1.1.41 (Isocitrate Dehydrogenase)
RN  - EC 1.1.1.41 (isocitrate dehydrogenase 2, human)
RN  - GAN16C9B8O (Glutathione)
SB  - IM
MH  - Animals
MH  - Apoptosis/genetics
MH  - Carcinoma, Hepatocellular/*drug therapy/metabolism/pathology
MH  - Endoplasmic Reticulum Stress/genetics
MH  - Folic Acid/genetics/*metabolism
MH  - Gene Expression Regulation, Neoplastic
MH  - Glutathione/metabolism
MH  - Heat-Shock Proteins/antagonists & inhibitors/*genetics
MH  - Hep G2 Cells
MH  - Homeostasis
MH  - Humans
MH  - Inhibitor of Apoptosis Proteins/antagonists & inhibitors/*genetics
MH  - Isocitrate Dehydrogenase/genetics
MH  - Liver Neoplasms/*drug therapy/metabolism/pathology
MH  - Mice
MH  - Mitochondria/metabolism/pathology
MH  - Oxidation-Reduction
MH  - Oxidative Stress/genetics
MH  - Proto-Oncogene Proteins c-bcl-2/genetics
MH  - Reactive Oxygen Species/metabolism
OTO - NOTNLM
OT  - Folic acid
OT  - hepatocellular carcinoma
OT  - mitochondrial isocitrate dehydrogenase
OT  - mitochondrial redox homeostasis
OT  - reactive oxygen species sinker proteins
OT  - redox regulator
EDAT- 2017/06/24 06:00
MHDA- 2017/07/14 06:00
CRDT- 2017/06/23 06:00
AID - 10.1177/1010428317702649 [doi]
PST - ppublish
SO  - Tumour Biol. 2017 Jun;39(6):1010428317702649. doi: 10.1177/1010428317702649.