| Article ID | Journal | Published Year | Pages | File Type |
|---|---|---|---|---|
| 1908950 | Free Radical Biology and Medicine | 2012 | 9 Pages |
Cancer cell survival is known to be related to the ability to counteract oxidative stress, and glutathione (GSH) depletion has been proposed as a mechanism to sensitize cells to anticancer therapy. However, we observed that GI-ME-N cells, a neuroblastoma cell line without MYCN amplification, are able to survive even if GSH-depleted by l-buthionine-(S,R)-sulfoximine (BSO). Here, we show that in GI-ME-N cells, BSO activates Nrf2 and up-regulates heme oxygenase-1 (HO-1). Silencing of Nrf2 restrained HO-1 induction by BSO. Inhibition of HO-1 and silencing of Nrf2 or HO-1 sensitized GI-ME-N cells to BSO, leading to reactive oxygen/nitrogen species overproduction and decreasing viability. Moreover, targeting the Nrf2/HO-1 axis sensitized GI-ME-N cells to etoposide more than GSH depletion. Therefore, we have provided evidence that in GI-ME-N cells, the Nrf2/HO-1 axis plays a crucial role as a protective factor against cellular stress, and we suggest that the inhibition of Nfr2/HO-1 signaling should be considered as a central target in the clinical battle against neuroblastoma.
Graphical abstractFigure optionsDownload full-size imageDownload high-quality image (96 K)Download as PowerPoint slideHighlights► GI-ME-N neuroblastoma cell survival is independent from GSH depletion by BSO. ► BSO activates Nrf2 and up-regulates heme oxygenase-1 (HO-1) in GI-ME-N cells. ► Inhibition of HO-1 and silencing of Nrf2 or HO-1 sensitizes GI-ME-N cells to BSO. ► Inhibition of Nrf2/HO-1 axis sensitizes GI-ME-N cells to etoposide more than BSO. ► Inhibition Nfr2/HO-1 should be a potential target in neuroblastoma therapy.
