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

Our plain-English summary of A Redox-Silent Analogue of Tocotrienol May Break the Homeostasis of Proteasomes in Human Malignant Mesothelioma Cells by Inhibiting STAT3 and NRF1, by K. Ishii, M. Fusegi, T. Mori, et al (International Journal of Molecular Sciences, 2022).

The study

• Authors: K. Ishii, M. Fusegi, T. Mori, K. Teshima, N. Ninomiya, K. Kohno, A. Sato, T. Ishida, Y. Miyakoshi, T. Yano
• Journal: International Journal of Molecular Sciences
• Published: 2022;23(5)
• Cited by: 6 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This laboratory study used two human malignant mesothelioma cell lines, H28 and H2452. It did not study patients or asbestos exposure. The authors tested α-T3E, a lab-made compound derived from tocotrienol, a form of vitamin E. Cisplatin, pemetrexed and their combination cut H28 cell viability by about 20, 50 and 50% respectively, but did not affect H2452 cells. At 20 micromolar, α-T3E cut the viability of both lines by more than 80%. It reduced proteasome activity; the proteasome is the cell's protein-disposal system. In H2452 cells it reduced STAT3 activation and lowered mRNA levels of several proteasome-subunit genes. The proteasome blockers bortezomib and marizomib raised active NRF1, a protein linked to proteasome recovery. With α-T3E, no significant change in active NRF1 was found. In α-T3E-treated H2452 cells, the endoplasmic reticulum stress protein CHOP averaged 17.20 times its starting level after 24 hours (three samples). The authors concluded that α-T3E caused cell death through these effects. They called it a promising candidate and said a clinical trial in patients is needed.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (in vitro) experiments on human malignant mesothelioma cell lines
• Who was studied: Two human malignant mesothelioma cell lines, H28 and H2452, obtained from ATCC. Most mechanism experiments used H2452 cells.
• Exposure: No asbestos exposure was studied. Cells were treated with the tocotrienol analogue α-T3E (0 to 20 micromolar) and with cisplatin, pemetrexed, their combination, bortezomib, marizomib and the STAT3 inhibitor niclosamide.
• Main results:
  • Cisplatin, pemetrexed and their combination reduced H28 cell viability by about 20, 50 and 50%, respectively, but did not affect H2452 cell viability.
  • 20 micromolar α-T3E reduced the viability of both cell lines by more than 80%.
  • α-T3E increased polyubiquitinated protein levels over time and significantly inhibited proteasome chymotrypsin-like activity. Polyubiquitinated proteins are a marker of proteasome inhibition.
  • In H2452 cells, α-T3E significantly reduced the mRNA levels of proteasome subunits PSMB1 to PSMB6 and slightly reduced PSMB7, as measured by real-time quantitative PCR.
  • Bortezomib and marizomib raised active NRF1 levels in H2452 cells. In α-T3E-treated cells, active NRF1 showed no significant difference from the control.
  • A high dose of bortezomib (100 nM) reduced H2452 cell viability by about 40%. The authors described this as markedly weaker than the effect of α-T3E.
  • In α-T3E-treated H2452 cells, the mean ratio of protein level at 24 hours to 0 hours (n = 3) was 8.92-fold for BIP, 17.20-fold for CHOP and 3.17-fold for IRE1α.
• The authors' conclusion: The authors concluded that α-T3E disrupted proteasome balance in chemoresistant mesothelioma cells by inactivating STAT3 and NRF1 together. In their view this led to severe ER stress and cell death. They said a clinical trial in mesothelioma patients is needed.
• Limitations the authors state:
  • The authors said their proposed explanation for how α-T3E blocks NRF1 activation (through NGLY1 and DDI2) is speculative and needs further study.
  • The authors said testing in patients is still required to establish α-T3E as a treatment.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma.

Related studies

• A redox-silent analogue of tocotrienol inhibits cobalt(II) chloride-induced VEGF expression via Yes signaling in mesothelioma cells — A. Sato, N. Virgona, et al. (2014)
• A Redox-Inactive Derivative of Tocotrienol Suppresses Tumor Growth of Mesothelioma Cells in a Xenograft Model — A. Sato, T. Arai, et al. (2019)
• A Succinate Ether Derivative of Tocotrienol Enhances Dickkopf-1 Gene Expression through Epigenetic Alterations in Malignant Mesothelioma Cells — A. Sato, H. Ueno, et al. (2018)
• A STAT3-NFkB/DDIT3/CEBPβ axis modulates ALDH1A3 expression in chemoresistant cell subpopulations — C. Canino, Y. Luo, et al. (2015)
• The tocotrienol-rich fraction from rice bran enhances cisplatin-induced cytotoxicity in human mesothelioma H28 cells — K. Nakashima, N. Virgona, et al. (2010)
• Modulation of reactive oxygen species via ERK and STAT3 dependent signalling are involved in the response of mesothelioma cells to exemestane — B. Nuvoli, E. Camera, et al. (2018)

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