Abstract
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.
Highlights
Introduction published maps and institutional affilMalignant mesothelioma (MM) is a highly aggressive tumor type that is typically caused by exposure to asbestos and has limited treatment options [1]
Inducing more than 80% decreases in the viabilities of these MM cell lines (Figure 1b). Since this treatment dose of α-T3E is within the maximum level in the plasma of mice treated with an adequate dose of α-T3E, which had no adverse effects and inhibited the in vivo growth of MM cells [14], α-T3E may function as an effective anti-mesothelioma agent in MM cells with strong chemoresistance
A recent study reports that signal transducer and activator of transcription 3 (STAT3) acts as a positive transcription factor to induce the expression of the main parts of proteasome subunits in cancer cells [6]
Summary
A recent study demonstrates that MM cells have strong chemoresistance against several types of anti-cancer agents [13]. Α-T3E exhibited effective cytotoxicity against the two MM cell lines in a dose-dependent manner, with 20 μM α-T3E inducing more than 80% decreases in the viabilities of these MM cell lines (Figure 1b) Since this treatment dose of α-T3E is within the maximum level in the plasma of mice treated with an adequate dose of α-T3E, which had no adverse effects and inhibited the in vivo growth of MM cells [14], α-T3E may function as an effective anti-mesothelioma agent in MM cells with strong chemoresistance.
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