TY - JOUR
T1 - Resistance of neuroblastoma GI-ME-N cell line to glutathione depletion involves Nrf2 and heme oxygenase-1
AU - Furfaro, Anna Lisa
AU - MacAy, José Raúl Zumba
AU - Marengo, Barbara
AU - Nitti, Mariapaola
AU - Parodi, Alessia
AU - Fenoglio, Daniela
AU - Marinari, Umberto Maria
AU - Pronzato, Maria Adelaide
AU - Domenicotti, Cinzia
AU - Traverso, Nicola
PY - 2012/1/15
Y1 - 2012/1/15
N2 - 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.
AB - 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.
KW - Cancer
KW - Etoposide
KW - Free radicals
KW - Glutathione
KW - Heme oxygenase-1
KW - Neuroblastoma
KW - Nrf2
KW - Oxidative stress
UR - http://www.scopus.com/inward/record.url?scp=84855427508&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84855427508&partnerID=8YFLogxK
U2 - 10.1016/j.freeradbiomed.2011.11.007
DO - 10.1016/j.freeradbiomed.2011.11.007
M3 - Article
C2 - 22142473
AN - SCOPUS:84855427508
VL - 52
SP - 488
EP - 496
JO - Free Radical Biology and Medicine
JF - Free Radical Biology and Medicine
SN - 0891-5849
IS - 2
ER -