A Redox-Silent Analogue of Tocotrienol May Break the Homeostasis of Proteasomes in Human Malignant Mesothelioma Cells by Inhibiting STAT3 and NRF1

Kyota Ishii,Momoka Fusegi, Tatsuki Mori, Kosuke Teshima, Nanako Ninomiya,Kakeru Kohno,Ayami Sato, Tatsuya Ishida,Yuichi Miyakoshi,Tomohiro Yano

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES(2022)

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摘要
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.
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关键词
cytotoxicity, ER stress, malignant mesothelioma cells, NRF1, proteasome inhibitor, redox-silent analogue, STAT3, tocotrienol
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