Laboratory of Molecular Bromacology, Graduate School of Food and Nutritional Sciences, Toyo University, Oura District, Gunma, Itakura Town 374-0193, Japan.
Department of Food and Life Sciences, Faculty of Food and Nutritional Sciences, Toyo University, Oura District, Gunma, Itakura Town 374-0193, Japan.
Int J Mol Sci. 2022 Feb 28;23(5):2655. doi: 10.3390/ijms23052655.
6--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.
6-羧丙基-α-生育三烯酚（α-T3E）是生育三烯酚的一种多靶点、无氧化还原活性的类似物，对许多癌细胞具有细胞毒性，包括恶性间皮瘤（MM）细胞。α-T3E 有几个分子靶点，可以有效地诱导 MM 细胞的细胞毒性；然而，这种细胞毒性的机制尚不清楚。在本研究中，我们证明了 α-T3E 依赖性的蛋白酶体稳态破坏强烈诱导内质网（ER）应激，从而对 MM 细胞产生有效的细胞毒性。α-T3E 依赖性的蛋白酶体稳态破坏依赖于蛋白酶体亚基的减少，这是通过信号转导和转录激活因子 3（STAT3）和红细胞生成素相关因子-1（NRF1）的失活来实现的，从而抑制蛋白酶体的蛋白酶活性，如糜蛋白酶样活性。α-T3E 依赖性的这种活性抑制也诱导严重的 ER 应激，并最终导致对具有化疗耐药性的 MM 细胞的有效细胞毒性。这些结果表明，α-T3E 通过同时失活 STAT3 和 NRF1 破坏蛋白酶体的内稳态，作为一种有效的抗间皮瘤药物发挥作用。
