PMID- 35269802
OWN - NLM
STAT- MEDLINE
DCOM- 20220408
LR  - 20220408
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 23
IP  - 5
DP  - 2022 Feb 28
TI  - A Redox-Silent Analogue of Tocotrienol May Break the Homeostasis of Proteasomes 
      in Human Malignant Mesothelioma Cells by Inhibiting STAT3 and NRF1.
LID - 10.3390/ijms23052655 [doi]
LID - 2655
AB  - 6-O-Carboxypropyl-alpha-tocotrienol (alpha-T3E) is a multi-target redox-silent 
      analogue of tocotrienol that exhibits cytotoxicity against many cancer cells, 
      including malignant mesothelioma (MM) cells. alpha-T3E has several molecular targets 
      to effectively induce cytotoxicity against MM cells; however, the mechanisms 
      underlying this cytotoxicity remain unclear. In the present study, we 
      demonstrated that the alpha-T3E-dependent disruption of the homeostasis of 
      proteasomes strongly induced endoplasmic reticulum (ER) stress, which resulted in 
      effective cytotoxicity against MM cells. The alpha-T3E-dependent disruption of the 
      homeostasis of proteasomes depended on decreases in proteasome subunits via the 
      inactivation of signal transducer and activator of transcription 3 (STAT3) and 
      nuclear factor erythroid 2 related factor-1 (NRF1), which inhibited protease 
      activity, such as chymotrypsin-like activity, in proteasomes. The alpha-T3E-dependent 
      inhibition of this activity also induced severe ER stress and ultimately resulted 
      in effective cytotoxicity against MM cells with chemoresistance. The present 
      results indicate that alpha-T3E acts as an effective anti-mesothelioma agent by 
      disrupting the homeostasis of proteasomes through the simultaneous inactivation 
      of STAT3 and NRF1.
FAU - Ishii, Kyota
AU  - Ishii K
AD  - Laboratory of Molecular Bromacology, Graduate School of Food and Nutritional 
      Sciences, Toyo University, Oura District, Gunma, Itakura Town 374-0193, Japan.
FAU - Fusegi, Momoka
AU  - Fusegi M
AD  - Laboratory of Molecular Bromacology, Graduate School of Food and Nutritional 
      Sciences, Toyo University, Oura District, Gunma, Itakura Town 374-0193, Japan.
FAU - Mori, Tatsuki
AU  - Mori T
AD  - Department of Food and Life Sciences, Faculty of Food and Nutritional Sciences, 
      Toyo University, Oura District, Gunma, Itakura Town 374-0193, Japan.
FAU - Teshima, Kosuke
AU  - Teshima K
AD  - Department of Food and Life Sciences, Faculty of Food and Nutritional Sciences, 
      Toyo University, Oura District, Gunma, Itakura Town 374-0193, Japan.
FAU - Ninomiya, Nanako
AU  - Ninomiya N
AD  - Department of Food and Life Sciences, Faculty of Food and Nutritional Sciences, 
      Toyo University, Oura District, Gunma, Itakura Town 374-0193, Japan.
FAU - Kohno, Kakeru
AU  - Kohno K
AD  - Research Institute of Life Innovation, Toyo University, Oura District, Gunma, 
      Itakura Town 374-0193, Japan.
FAU - Sato, Ayami
AU  - Sato A
AD  - Research Institute of Life Innovation, Toyo University, Oura District, Gunma, 
      Itakura Town 374-0193, Japan.
FAU - Ishida, Tatsuya
AU  - Ishida T
AD  - Research Institute of Life Innovation, Toyo University, Oura District, Gunma, 
      Itakura Town 374-0193, Japan.
FAU - Miyakoshi, Yuichi
AU  - Miyakoshi Y
AD  - Research Institute of Life Innovation, Toyo University, Oura District, Gunma, 
      Itakura Town 374-0193, Japan.
FAU - Yano, Tomohiro
AU  - Yano T
AUID- ORCID: 0000-0002-9490-3424
AD  - Research Institute of Life Innovation, Toyo University, Oura District, Gunma, 
      Itakura Town 374-0193, Japan.
LA  - eng
GR  - 18K11058/Japan Society for the Promotion of Science/
PT  - Journal Article
DEP - 20220228
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - 0 (STAT3 Transcription Factor)
RN  - 0 (STAT3 protein, human)
RN  - 0 (Tocotrienols)
RN  - EC 3.4.25.1 (Proteasome Endopeptidase Complex)
SB  - IM
MH  - Cell Line, Tumor
MH  - Homeostasis
MH  - Humans
MH  - *Mesothelioma/drug therapy/pathology
MH  - *Mesothelioma, Malignant
MH  - Oxidation-Reduction
MH  - Proteasome Endopeptidase Complex/metabolism
MH  - STAT3 Transcription Factor
MH  - *Tocotrienols/pharmacology
PMC - PMC8910454
OTO - NOTNLM
OT  - ER stress
OT  - NRF1
OT  - STAT3
OT  - cytotoxicity
OT  - malignant mesothelioma cells
OT  - proteasome inhibitor
OT  - redox-silent analogue
OT  - tocotrienol
COIS- The authors declare no conflict of interest.
EDAT- 2022/03/11 06:00
MHDA- 2022/04/09 06:00
PMCR- 2022/02/28
CRDT- 2022/03/10 15:36
PHST- 2022/02/03 00:00 [received]
PHST- 2022/02/25 00:00 [revised]
PHST- 2022/02/26 00:00 [accepted]
PHST- 2022/03/10 15:36 [entrez]
PHST- 2022/03/11 06:00 [pubmed]
PHST- 2022/04/09 06:00 [medline]
PHST- 2022/02/28 00:00 [pmc-release]
AID - ijms23052655 [pii]
AID - ijms-23-02655 [pii]
AID - 10.3390/ijms23052655 [doi]
PST - epublish
SO  - Int J Mol Sci. 2022 Feb 28;23(5):2655. doi: 10.3390/ijms23052655.