Induction of endogenous Bcl-xS through the control of Bcl-x pre-mRNA splicing by antisense oligonucleotides

Resistance to apoptosis, which plays an important role in tumors that are r efractory to chemotherapy, is regulated by the ratio of antiapoptotic to pr oapoptotic proteins. By manipulating levels of these proteins, cells can be come sensitized to undergo apoptosis in response to chemotherapeutic agents . Alternative splicing of the bcl-x gene gives rise to two proteins with an tagonistic functions: Bcl-xL, a well-characterized antiapoptotic protein, a nd Bcl-xS, a proapoptotic protein. We show here that altering the ratio of Bcl-xL to Bcl-xS in the cell using an antisense oligonucleotide permitted c ells to be sensitized to undergo apoptosis in response to ultraviolet B rad iation and chemotherapeutic drug treatment. These results demonstrate the a bility of a chemically modified oligonucleotide to alter splice site select ion in an endogenous gene and illustrate a powerful tool to regulate cell s urvival.