A redox-silent analogue of tocotrienol inhibits cobalt(II) chloride-induced VEGF expression via Yes signaling in mesothelioma cells

Our plain-English summary of A redox-silent analogue of tocotrienol inhibits cobalt(II) chloride-induced VEGF expression via Yes signaling in mesothelioma cells, by A. Sato, N. Virgona, A. Ando, et al (Biological & Pharmaceutical Bulletin, 2014).

The study

• Authors: A. Sato, N. Virgona, A. Ando, M. Ota, T. Yano
• Journal: Biological & Pharmaceutical Bulletin
• Published: 2014;37(5):865-70
• Cited by: 7 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Vascular endothelial growth factor (VEGF) plays a crucial role in tumor angiogenesis and represents an attractive anticancer target. We have previously demonstrated that a redox-silent analogue of α-tocotrienol, 6-O-carboxypropyl-α-tocotrienol (T3E) exhibits potent anti-carcinogenic property in human malignant mesothelioma (MM) cells. However, inhibition of tumor growth by targeting VEGF pathway remains undetermined. In this study, we explored the inhibitory effect of T3E on the paracrine secretion of VEGF in MM cells under mimicked hypoxia by cobalt chloride (CoCl2). In this study we examine whether T3E can suppress the secretion of VEGF in MM cells exposed to mimic hypoxia by cobalt chloride (CoCl2). We found that CoCl2-induced hypoxia treatment leads to increased up-regulated hypoxia-inducible factor-2α (HIF-2α) and subsequently induced the secretion of VEGF in MM cells. This up-regulation activation mainly depended on the activation of Yes, a member of the Src family of kinases. Treatment of hypoxic MM cells with T3E effectively inhibited the secretion of VEGF, On the other hand, T3E inhibited CoCl2-induced gene expression of VEGF due to the inactivation of Yes/HIF-2α signaling. These data suggest that Yes/HIF2-α/VEGF could be a promising therapeutic target of T3E in MM cells.

In plain English

This laboratory study used one human mesothelioma cell line, H2452, grown in culture dishes. It did not study asbestos or people. The authors used cobalt chloride (CoCl2) to imitate low-oxygen conditions. They then tested T3E, a lab-made relative of the vitamin E form tocotrienol, on the cells' production of VEGF, a signal that helps tumors grow new blood vessels. They also used a gene-silencing tool against a protein called Yes. CoCl2 raised levels of the protein HIF-2α and of VEGF, and at 100 µM it significantly lowered cell survival. T3E at 20 µM, but not 10 µM, mostly suppressed the CoCl2-driven rise in VEGF and largely cancelled Yes activation and HIF-2α build-up. The same 20 µM dose also significantly reduced cell survival. Silencing Yes lowered HIF-2α and VEGF in CoCl2-treated cells. The authors concluded that T3E might be a candidate agent for treating malignant mesothelioma by blocking this signaling chain, and that it should be studied in living animals. Results are shown mainly in figures without exact values in the text.

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 cell-culture experiment (published as a Note)
• Who was studied: a single human mesothelioma cell line, H2452, obtained from ATCC; no patients or animals
• Exposure: cobalt chloride (CoCl2, 50 to 100 µM; 75 µM in main experiments) to mimic hypoxia, the tocotrienol analogue T3E (10 and 20 µM), and siRNA against Yes; asbestos was not studied
• Main results:
  • CoCl2 tended to lower cell viability as the dose rose, but the drop was statistically significant only at 100 µM compared with untreated cells
  • CoCl2 raised HIF-2α in a dose-dependent manner. It raised VEGF mRNA, which levelled off at 75 µM
  • Only the 20 µM dose of T3E significantly reduced cell viability, both with and without CoCl2
  • In CoCl2-treated cells, the rise in VEGF mRNA and VEGF secretion was mostly suppressed only by 20 µM T3E, with a significant difference. Lower doses did not affect VEGF
  • Without CoCl2, no dose of T3E affected VEGF mRNA or VEGF secretion
  • In CoCl2-treated cells, 20 µM T3E almost cancelled the CoCl2-induced activation of Yes and build-up of HIF-2α
  • In CoCl2-treated cells, silencing Yes with siRNA reduced HIF-2α protein, VEGF mRNA and VEGF secretion
  • Under the hypoxia condition, the authors detected HIF-2α but not HIF-1α in H2452 cells
• The authors' conclusion: The authors concluded that T3E might be a useful candidate agent for treating malignant mesothelioma because it blocks Yes/HIF-2α/VEGF signaling, and that it should be investigated in further in vivo study
• Limitations the authors state:
  • The authors state that T3E still needs to be tested in living organisms (in vivo)

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, Angiogenesis, Carcinogenic, Hypoxia.

Related studies

• 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)
• Yes is a central mediator of cell growth in malignant mesothelioma cells — A. Sato, M. Sekine, et al. (2012)
• The tocotrienol-rich fraction from rice bran enhances cisplatin-induced cytotoxicity in human mesothelioma H28 cells — K. Nakashima, N. Virgona, et al. (2010)
• Mitogenic and apoptotic signaling by carotenoids: involvement of a redox mechanism — P. Palozza, S. Serini, et al. (2001)
• Reactive oxygen species and PI3K/Akt signaling play key roles in the induction of Nrf2-driven heme oxygenase-1 expression in sulforaphane-treated human mesothelioma MSTO-211H cells — Y.J. Lee, H.Y. Jeong, et al. (2012)

Browse more research in Biological & Pharmaceutical Bulletin, or return to medical research.