A moderate reduction of Bcl-x_L expression protects against tumorigenesis; However, it also increases susceptibility to tissue injury

Little consideration has been given to the possibility that there could be variations in protein expression that alter susceptibility to tumorigenesis without causing other obvious phenotypic effects. Therefore, we sought to determine if haploinsufficiency for the antiapoptotic protein Bcl-x_L would affect tumorigenesis. We chose to study Bcl-x_L because although bcl-x^+/- mice were thought to be phenotypically normal, we and others found that haploinsufficiency for Bcl-x_L lowers fibroblast resistance to apoptosis in tissue culture. Since resistance to certain forms of apoptosis is required for tumor formation, this suggested that decreased Bcl-x_L expression would afford protection against tumorigenesis. Indeed, we demonstrate here that bcl-x^+/- mice are strikingly resistant to carcinogen-induced tumorigenesis. However, we found that they pay a price for their resistance in that they are more susceptible to clinically relevant forms of tissue injury - they suffer increased hepatic injury in a model of binge alcohol abuse and in response to TNF-α treatment. These findings are important because they suggest that even minor variations in Bcl-x_L expression could affect susceptibility to cancer and other diseases. Additionally, they indicate that the potential for increased susceptibility to tissue injury must be considered in the design of chemopreventative and antineoplastic strategies that involve inhibition of Bcl-x_L activity.