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.

Todaro, M., Lombardo, Y., Francipane, M.G., Perez Alea, M., Cammareri, P., Iovino, F., et al. (2008). Apoptosis resistance in epithelial tumors is mediated by tumor-cell-derived interleukin-4. CELL DEATH AND DIFFERENTIATION, 15(4), 762-772 [10.1038/sj.cdd.4402305].

Apoptosis resistance in epithelial tumors is mediated by tumor-cell-derived interleukin-4

TODARO, Matilde;LOMBARDO, Ylenia;FRANCIPANE, Maria Giovanna;PEREZ ALEA, Milidys;CAMMARERI, Patrizia;IOVINO, Flora;DI STEFANO, Anna Barbara;DI BERNARDO, Cristoforo;AGRUSA, Antonino;STASSI, Giorgio
2008

Abstract

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.
Settore MED/04 - Patologia Generale
Todaro, M., Lombardo, Y., Francipane, M.G., Perez Alea, M., Cammareri, P., Iovino, F., et al. (2008). Apoptosis resistance in epithelial tumors is mediated by tumor-cell-derived interleukin-4. CELL DEATH AND DIFFERENTIATION, 15(4), 762-772 [10.1038/sj.cdd.4402305].
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/10447/60168
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