Therapeutic Conversion of Viability Promoting MCL1 to Death-Inducing Forms: A Novel Strategy for Breast Cancer

摘要

The BCL2 family member MCL1 is expressed in breast cancer cells in its full-length, anti-apoptotic form. The goal of this project was to induce conversion of MCL1 to pro-apoptotic forms as a means of enhancing the death of these cells. The approach was identify means of inducing alternate splicing of MCL1 using antisense oligonucleotides, since splice variants are known to promote cell death rather than cell survival. We identified reagents and conditions that result in decreased expression of the antiapoptotic MCL1L protein and increased expression of proapoptotic splice variants. These splice- switching agents inhibited tumor cell growth, and did so in a more sustained fashion than siRNA directed against MCL1L. Reagents that induce splice switching of MCL1 thus have promise for further development for the treatment of breast cancer.