PMID- 32696316
OWN - NLM
STAT- MEDLINE
DCOM- 20210623
LR  - 20211002
IS  - 1573-7217 (Electronic)
IS  - 0167-6806 (Print)
IS  - 0167-6806 (Linking)
VI  - 183
IP  - 3
DP  - 2020 Oct
TI  - Lysine oxidase exposes a dependency on the thioredoxin antioxidant pathway in 
      triple-negative breast cancer cells.
PG  - 549-564
LID - 10.1007/s10549-020-05801-4 [doi]
AB  - PURPOSE: Transformed cells are vulnerable to depletion of certain amino acids. 
      Lysine oxidase (LO) catalyzes the oxidative deamination of lysine, resulting in 
      lysine depletion and hydrogen peroxide production. Although LO has broad 
      antitumor activity in preclinical models, the cytotoxic mechanisms of LO are 
      poorly understood. METHODS: Triple (ER/PR/HER2)-negative breast cancer (TNBC) 
      cells were treated with control media, lysine-free media or control media 
      supplemented with LO and examined for cell viability, caspase activation, 
      induction of reactive oxygen species (ROS) and antioxidant signaling. To 
      determine the role of nuclear factor erythroid 2-related factor 2 (NRF2) and 
      thioredoxin reductase-1 (TXNRD1) in LO-induced cell death, NRF2 and TXNRD1 were 
      individually silenced by RNAi. Additionally, the pan-TXNRD inhibitor auranofin 
      was used in combination with LO. RESULTS: LO activates caspase-independent cell 
      death that is suppressed by necroptosis and ferroptosis inhibitors, which are 
      inactive against lysine depletion, pointing to fundamental differences between LO 
      and lysine depletion. LO rapidly induces ROS with a return to baseline levels 
      within 24 h that coincides temporally with induction of TXNRD activity, the 
      rate-limiting enzyme in the thioredoxin antioxidant pathway. ROS induction is 
      required for LO-mediated cell death and NRF2-dependent induction of TXNRD1. 
      Silencing NRF2 or TXNRD1 enhances the cytotoxicity of LO. The pan-TXNRD inhibitor 
      auranofin is synergistic with LO against transformed breast epithelial cells, but 
      not untransformed cells, underscoring the tumor-selectivity of this strategy. 
      CONCLUSIONS: LO exposes a redox vulnerability of TNBC cells to TXNRD inhibition 
      by rendering tumor cells dependent on the thioredoxin antioxidant pathway for 
      survival.
FAU - Chepikova, Olga E
AU  - Chepikova OE
AD  - Department of Medicine, University of Wisconsin Carbone Cancer Center, University 
      of Wisconsin-Madison, MFCB 4144, 1685 Highland Avenue, Madison, WI, 53705, USA.
AD  - Institute of Molecular Medicine, Sechenov First Moscow State Medical University, 
      Moscow, Russia.
FAU - Malin, Dmitry
AU  - Malin D
AD  - Department of Medicine, University of Wisconsin Carbone Cancer Center, University 
      of Wisconsin-Madison, MFCB 4144, 1685 Highland Avenue, Madison, WI, 53705, USA.
FAU - Strekalova, Elena
AU  - Strekalova E
AD  - Department of Medicine, University of Wisconsin Carbone Cancer Center, University 
      of Wisconsin-Madison, MFCB 4144, 1685 Highland Avenue, Madison, WI, 53705, USA.
FAU - Lukasheva, Elena V
AU  - Lukasheva EV
AD  - Peoples' Friendship, University of Russia (RUDN University), Moscow, Russia.
FAU - Zamyatnin, Andrey A Jr
AU  - Zamyatnin AA Jr
AD  - Institute of Molecular Medicine, Sechenov First Moscow State Medical University, 
      Moscow, Russia.
AD  - Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State 
      University, Moscow, Russia.
FAU - Cryns, Vincent L
AU  - Cryns VL
AUID- ORCID: 0000-0003-0355-2268
AD  - Department of Medicine, University of Wisconsin Carbone Cancer Center, University 
      of Wisconsin-Madison, MFCB 4144, 1685 Highland Avenue, Madison, WI, 53705, USA. 
      vlcryns@medicine.wisc.edu.
LA  - eng
GR  - P30 CA014520/CA/NCI NIH HHS/United States
GR  - P30CA14520/CA/NCI NIH HHS/United States
PT  - Journal Article
DEP - 20200721
PL  - Netherlands
TA  - Breast Cancer Res Treat
JT  - Breast cancer research and treatment
JID - 8111104
RN  - 0 (Antioxidants)
RN  - 0 (Reactive Oxygen Species)
RN  - 52500-60-4 (Thioredoxins)
RN  - EC 1.- (Oxidoreductases)
RN  - K3Z4F929H6 (Lysine)
SB  - IM
MH  - Antioxidants/pharmacology
MH  - Humans
MH  - Lysine
MH  - Oxidative Stress
MH  - Oxidoreductases
MH  - Reactive Oxygen Species
MH  - Thioredoxins/genetics/metabolism
MH  - *Triple Negative Breast Neoplasms/drug therapy/genetics
PMC - PMC7501192
MID - NIHMS1613883
OTO - NOTNLM
OT  - Metabolism
OT  - Oxidative stress
OT  - Therapeutics
OT  - Tumor dependency
COIS- Compliance with ethical standards Conflict of interest The authors declare that 
      they have no conflict of interest.
EDAT- 2020/07/23 06:00
MHDA- 2021/06/24 06:00
PMCR- 2021/10/01
CRDT- 2020/07/23 06:00
PHST- 2020/03/14 00:00 [received]
PHST- 2020/07/11 00:00 [accepted]
PHST- 2020/07/23 06:00 [pubmed]
PHST- 2021/06/24 06:00 [medline]
PHST- 2020/07/23 06:00 [entrez]
PHST- 2021/10/01 00:00 [pmc-release]
AID - 10.1007/s10549-020-05801-4 [pii]
AID - 10.1007/s10549-020-05801-4 [doi]
PST - ppublish
SO  - Breast Cancer Res Treat. 2020 Oct;183(3):549-564. doi: 
      10.1007/s10549-020-05801-4. Epub 2020 Jul 21.