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

Autor: Ishii, Kyota, Fusegi, Momoka, Mori, Tatsuki, Teshima, Kosuke, Ninomiya, Nanako, Kohno, Kakeru, Sato, Ayami, Ishida, Tatsuya, Miyakoshi, Yuichi, Yano, Tomohiro
Předmět:
Zdroj: International Journal of Molecular Sciences; Mar2022, Vol. 23 Issue 5, p2655, 1p
Abstrakt: 6-O-Carboxypropyl-alpha-tocotrienol (α-T3E) is a multi-target redox-silent analogue of tocotrienol that exhibits cytotoxicity against many cancer cells, including malignant mesothelioma (MM) cells. α-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 α-T3E-dependent disruption of the homeostasis of proteasomes strongly induced endoplasmic reticulum (ER) stress, which resulted in effective cytotoxicity against MM cells. The α-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 α-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 α-T3E acts as an effective anti-mesothelioma agent by disrupting the homeostasis of proteasomes through the simultaneous inactivation of STAT3 and NRF1. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje