PMID- 31979226
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20200930
IS  - 2072-6694 (Print)
IS  - 2072-6694 (Electronic)
IS  - 2072-6694 (Linking)
VI  - 12
IP  - 2
DP  - 2020 Jan 23
TI  - Targeting NRF2-Governed Glutathione Synthesis for SDHB-Mutated Pheochromocytoma 
      and Paraganglioma.
LID - 10.3390/cancers12020280 [doi]
LID - 280
AB  - Succinate dehydrogenase subunit B (SDHB) deficiency frequently occurs in cluster 
      I pheochromocytomas and paragangliomas (PCPGs). SDHB-mutated PCPGs are 
      characterized by alterations in the electron transport chain, metabolic 
      reprogramming of the tricarboxylic cycle, and elevated levels of reactive oxygen 
      species (ROS). We discovered that SDHB-deficient PCPG cells exhibit increased 
      oxidative stress burden, which leads to elevated demands for glutathione 
      metabolism. Mechanistically, nuclear factor erythroid 2-related factor 2 
      (NRF2)-guided glutathione de novo synthesis plays a key role in supporting 
      cellular survival and the proliferation of SDHB-knockdown (SDHB(KD)) cells. NRF2 
      blockade not only disrupted ROS homeostasis in SDHB-deficient cells but also 
      caused severe cytotoxicity by the accumulation of DNA oxidative damage. Brusatol, 
      a potent NRF2 inhibitor, showed a promising effect in suppressing SDHB(KD) 
      metastatic lesions in vivo, with prolonged overall survival in mice bearing PCPG 
      allografts. Our findings highlight a novel therapeutic strategy of targeting the 
      NRF2-driven glutathione metabolic pathway against SDHB-mutated PCPG.
FAU - Liu, Yang
AU  - Liu Y
AD  - Neuro-Oncology Branch Center for Cancer Research, National Cancer Institute, 
      Bethesda, MD 20892, USA.
FAU - Pang, Ying
AU  - Pang Y
AD  - Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute 
      of Child Health and Human Development, National Institutes of Health, Bethesda, 
      MD 20892, USA.
FAU - Caisova, Veronika
AU  - Caisova V
AD  - Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute 
      of Child Health and Human Development, National Institutes of Health, Bethesda, 
      MD 20892, USA.
FAU - Ding, Jianyi
AU  - Ding J
AD  - Neuro-Oncology Branch Center for Cancer Research, National Cancer Institute, 
      Bethesda, MD 20892, USA.
FAU - Yu, Di
AU  - Yu D
AD  - Neuro-Oncology Branch Center for Cancer Research, National Cancer Institute, 
      Bethesda, MD 20892, USA.
FAU - Zhou, Yiqiang
AU  - Zhou Y
AD  - Neuro-Oncology Branch Center for Cancer Research, National Cancer Institute, 
      Bethesda, MD 20892, USA.
FAU - Huynh, Thanh-Truc
AU  - Huynh TT
AD  - Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute 
      of Child Health and Human Development, National Institutes of Health, Bethesda, 
      MD 20892, USA.
FAU - Ghayee, Hans
AU  - Ghayee H
AD  - Division of Endocrinology, Department of Medicine, University of Florida, 
      Gainesville, FL 32610, USA.
AD  - Malcom Randall VA Medical Center, Gainesville, FL 32608, USA.
FAU - Pacak, Karel
AU  - Pacak K
AD  - Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute 
      of Child Health and Human Development, National Institutes of Health, Bethesda, 
      MD 20892, USA.
FAU - Yang, Chunzhang
AU  - Yang C
AD  - Neuro-Oncology Branch Center for Cancer Research, National Cancer Institute, 
      Bethesda, MD 20892, USA.
LA  - eng
PT  - Journal Article
DEP - 20200123
PL  - Switzerland
TA  - Cancers (Basel)
JT  - Cancers
JID - 101526829
PMC - PMC7072390
OTO - NOTNLM
OT  - NRF2
OT  - SDHB mutation
OT  - glutathione metabolism
OT  - paraganglioma
OT  - pheochromocytoma
COIS- The authors declare no conflict of interest.
EDAT- 2020/01/26 06:00
MHDA- 2020/01/26 06:01
PMCR- 2020/01/23
CRDT- 2020/01/26 06:00
PHST- 2020/01/14 00:00 [received]
PHST- 2020/01/20 00:00 [revised]
PHST- 2020/01/21 00:00 [accepted]
PHST- 2020/01/26 06:00 [entrez]
PHST- 2020/01/26 06:00 [pubmed]
PHST- 2020/01/26 06:01 [medline]
PHST- 2020/01/23 00:00 [pmc-release]
AID - cancers12020280 [pii]
AID - cancers-12-00280 [pii]
AID - 10.3390/cancers12020280 [doi]
PST - epublish
SO  - Cancers (Basel). 2020 Jan 23;12(2):280. doi: 10.3390/cancers12020280.