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

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.

Understanding the Transcription Factor NFE2L1/NRF1 from the Perspective of Hallmarks of Cancer

“…In another TNBC study, proteasome subunit cleavage site-specific inhibitor treatments and CRISPR/Cas9-mediated genetic inhibition of proteasome subunit cleavage site-suppressed NFE2L1 activity and mediated proteasome subunit induction, and prevented "bounce-back" effect in vitro and in vivo [124]. Six-O-carboxypropyl-αtocotrienol (α-T3E), a redox-silent analogue of tocotrienols, was shown to disrupt proteasome homeostasis by inactivating NFE2L1, eventually inducing severe ER stress and increasing the sensitivity of chemoresistance (cisplatin) in malignant mesothelioma cells [125].…”

Unravelling the role of NFE2L1 in stress responses and related diseases

“…Subsequently, mTORC1 prompts NFE2L1 activation to enhance proteasome synthesis and ERAD [ 57 ]. Moreover, STAT3, another transcription factor promoting NFE2L1 expression, could be activated by both mTORC1 and ROS, thereby contributing to NFE2L1 induction under ER stress [ 14 , 125 ]. In addition, the nutrient-sensing pathway named AMPK signalling may antagonize NFE2L1 since AMPK can impede mTORC1 signalling by maintaining TSC1/2 activity [ 126 ].…”

“…Numerous novel studies have been performed on the regulatory molecules and pathways associated with NFE2L1 as a biomarker and therapeutic target in various tumors ( Table 1 ) [ 123 , 125 , [145] , [146] , [147] , [148] ]. The antioxidant stress response cascades mediated by NFE2L1 hold great promise as effective targets for tumour therapy, and the concurrent inhibition of proteasomes and NFE2L1 has been proven to enhance the therapeutic efficacy against malignancies.…”

“…For instance, MG132 downregulates Proteasome 20S Subunit Beta 2 (PSMB2) to hinder NFE2L1 activation and impede the gastric cells proliferation by suppressing proteasome activity [ 123 ]. In terms of malignant mesothelioma, α-T3E exerts cytotoxic effects on chemoresistant H2452 cells by inactivating NFE2L1, inducing ER stress, and disrupting proteasome homeostasis [ 125 ]. Another recent study substantiated that NFE2L1 can induce p62, a Ub receptor for autophagy, to diminish aggregated ubiquitinated proteins and prolong cell survival under proteasome inhibition in neuroblastoma cells, implying the potential of NFE2L1 inhibitors as therapeutic targets for neuroblastoma [ 143 ].…”

α-Tocotrienol and Redox-Silent Analogs of Vitamin E Enhances Bortezomib Sensitivity in Solid Cancer Cells through Modulation of NFE2L1

“…While vitamin E is well regarded as useful for cancer prevention due to its antioxidant effect, tocotrienols, a member of the vitamin E family, and redox-silent analogs of vitamin E such as α-tocopheryl succinate (TOS) and 6-O-Carboxypropyl-alpha-tocotrienol (T3E) are also known to exhibit anticancer effects via inhibition of specific cancer-related molecules such as HIF, Src, and STAT3 [22][23][24][25][26][27]. Furthermore, previous studies have reported that γ-tocotrienol and T3E modulate the expression levels of some proteasome-component proteins regulated by NFE2L1 [28,29]. Therefore, vitamin E and its redox-silent analogs may affect NFE2L1.…”