**1. Introduction**

A proteasome is an enzyme complex that plays a role in degrading specific proteins and unnecessary proteins in the cells [1]. Since cancer cells have high expression of proteasome component proteins and higher proteasome activity than normal cells, proteasome may be important for cancer survival and proliferation [2–6]. In accordance with this, proteasome inhibitors (PIs) are known to induce effective cell death and anti-proliferation effect in some cancer cells, with some PIs in use as anticancer drugs for blood cancers like multiple myeloma [7]. Furthermore, PIs are also expected to have therapeutic effects against solid cancers, and the efficacy of PIs in several solid cancers has been investigated. However, some clinical studies have concluded that PIs are ineffectual in the treatment of solid cancers, and it is regarded that solid cancers have PI resistance [8–13].

Recently, Nuclear factor erythroid 2-related factor-1 (NFE2L1) has been identified as a protein involved in PI resistance in cancer cells [14–17]. NFE2L1 is initially present on the endoplasmic reticulum membrane (~120 kDa), and it is released from the endoplasmic reticulum to the cytoplasm by NGLY1, p97 and Hrd1 [18–20]. When proteasome activity is sufficient, cytoplasmic NFE2L1 is generally degraded by the proteasome. However, when the functions of proteasomes are impaired, cytoplasmic NFE2L1 is stabilized and processed into a mature form (~110 kDa) by DDI2 [15,16]. Mature NFE2L1 translocates to the nucleus and induces the expression of proteasome-related genes [21]. They then ultimately recover proteasome activity. Given these facts, the finding of inhibitors of NFE2L1 may lead to improved sensitivity to PI in solid tumors. However, the screening for inhibitors of NFE2L1 has not progressed well.

**Citation:** Ishii, K.; Hido, M.; Sakamura, M.; Virgona, N.; Yano, T. α-Tocotrienol and Redox-Silent Analogs of Vitamin E Enhances Bortezomib Sensitivity in Solid Cancer Cells through Modulation of NFE2L1. *Int. J. Mol. Sci.* **2023**, *24*, 9382. https://doi.org/10.3390/ ijms24119382

Academic Editors: Barbara De Filippis, Alessandra Ammazzalorso and Marialuigia Fantacuzzi

Received: 2 May 2023 Revised: 23 May 2023 Accepted: 24 May 2023 Published: 27 May 2023

**Copyright:** © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

Vitamin E is a kind of phytochemical that has a long-term historical relationship to cancer. 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 [22–27]. 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.

In this study, we demonstrate that α-tocotrienol (T3), TOS, and T3E enhance sensitivity to bortezomib, a proteasome inhibitor, in solid cancer cells through modulating protein levels of NFE2L1.
