TY - JOUR
T1 - Apoptosis resistance in epithelial tumors is mediated by tumor-cell-derived interleukin-4
AU - Stassi, Giorgio
AU - Todaro, Matilde
AU - Agrusa, Antonino
AU - Iovino, Flora
AU - Perez Alea, Milidys
AU - Di Stefano, Anna Barbara
AU - Francipane, Maria Giovanna
AU - Lombardo, Ylenia
AU - Walczak, null
AU - Condorelli, null
PY - 2008
Y1 - 2008
N2 - We investigated the mechanisms involved in the resistance to cell death observed in epithelial cancers. Here, we identify that
primary epithelial cancer cells from colon, breast and lung carcinomas express high levels of the antiapoptotic proteins PED,
cFLIP, Bcl-xL and Bcl-2. These cancer cells produced interleukin-4 (IL-4), which amplified the expression levels of these
antiapoptotic proteins and prevented cell death induced upon exposure to TRAIL or other drug agents. IL-4 blockade resulted in
a significant decrease in the growth rate of epithelial cancer cells and sensitized them, both in vitro and in vivo, to apoptosis
induction by TRAIL and chemotherapy via downregulation of the antiapoptotic factors PED, cFLIP, Bcl-xL and Bcl-2.
Furthermore, we provide evidence that exogenous IL-4 was able to upregulate the expression levels of these antiapoptotic
proteins and potently stabilized the growth of normal epithelial cells rendering them apoptosis resistant. In conclusion, IL-4 acts
as an autocrine survival factor in epithelial cells. Our results indicate that inhibition of IL-4/IL-4R signaling may serve as a novel
treatment for epithelial cancers.
AB - We investigated the mechanisms involved in the resistance to cell death observed in epithelial cancers. Here, we identify that
primary epithelial cancer cells from colon, breast and lung carcinomas express high levels of the antiapoptotic proteins PED,
cFLIP, Bcl-xL and Bcl-2. These cancer cells produced interleukin-4 (IL-4), which amplified the expression levels of these
antiapoptotic proteins and prevented cell death induced upon exposure to TRAIL or other drug agents. IL-4 blockade resulted in
a significant decrease in the growth rate of epithelial cancer cells and sensitized them, both in vitro and in vivo, to apoptosis
induction by TRAIL and chemotherapy via downregulation of the antiapoptotic factors PED, cFLIP, Bcl-xL and Bcl-2.
Furthermore, we provide evidence that exogenous IL-4 was able to upregulate the expression levels of these antiapoptotic
proteins and potently stabilized the growth of normal epithelial cells rendering them apoptosis resistant. In conclusion, IL-4 acts
as an autocrine survival factor in epithelial cells. Our results indicate that inhibition of IL-4/IL-4R signaling may serve as a novel
treatment for epithelial cancers.
UR - http://hdl.handle.net/10447/55547
M3 - Article
VL - 15
SP - 762
EP - 772
JO - Cell Death and Differentiation
JF - Cell Death and Differentiation
SN - 1350-9047
ER -