Visit our Expo - Redox and Inflammation signaling 2012

Session XVII : Cell signaling in health and disease Poster XVII, 52
N-(4-hydroxyphenyl)retinamide interferes with functionally active IGF-1-mediated
survival pathways in human retinoblastoma cells.
Roberta Venè1, Giuseppe Arena1, Douglas M. Noonan2, Adriana Albini,1 and
Francesca Tosetti1
1Experimental Oncology A Laboratory, National Cancer Research Institute (IST), L.go
R. Benzi 10, 16132 Genova, Italy. 2Università degli Studi dell'Insubria, Varese, Italy. Email:
francesca.tosetti@istge.it , roberta.vene@istge.it
The cancer chemopreventive retinoid N-(4-hydroxyphenyl)retinamide (4HPR) kills Y79
retinoblastoma cells through a complex cell death pathway involving ROS elevation,
lysosomal damage and irreversible mitochondrial dysfunction. The Insulin-like growth factor
I (IGF-I) sustains the survival of tumor cells by different mechanisms including protection
from cell death and resistance to chemotherapeutic agents. Since IGF-I is also a survival
factor in the human retina, we asked whether IGF-I was able to protect Y79 cells against
4HPR cytotoxicity. IGF-I increased Y79 cell proliferation, in contrast, IGF-I could not
prevent 4HPR-induced DNA fragmentation, loss of MTT reduction, LDH release, and late
ATP depletion. IGF-I induced a rapid phosphorylation of AKT at Ser473 and mTOR at
Ser2448 that were sustained over time. Phosphorylation of AKT, but not of mTOR , was
almost completely suppressed by 4HPR at 24h. To confirm AKT inactivation by 4HPR, we
considered GSK3beta, a downstream substrate of AKT that is inactivated by phosphorylation
at Ser9 and is involved in the survival response induced by a number of growth factors and
chemical inhibitors of mitochondrial membrane depolarization. Surprisingly, we found that
not only 4HPR sustains IGF-I-induced GSK3beta phosphorylation at Ser9, but that 4HPR
itself is able to induce GSK3beta phosphorylation. The antioxidant NAC reversed this effect,
suggesting the involvement of a ROS-mediated mechanism in stimulation of GSK3 beta
phosphorylation by 4HPR.
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