Clusterin is a ubiquitously expressed
glycoprotein with multiple binding partners including
IL-6, Ku70, and Bax.
Clusterin blocks apoptosis by binding to activated Bax and sequestering it in the cytoplasm, thereby preventing Bax from entering mitochondria, releasing
cytochrome c, and triggering apoptosis. Because increased
clusterin expression correlates with aggressive behavior in
tumors,
clusterin inhibition might be beneficial in
cancer treatment. Our recent findings indicated that, in
neuroblastoma cells, cytoplasmic Bax also binds to Ku70; when Ku70 is acetylated, Bax is released and can initiate cell death. Therefore, increasing Ku70 acetylation, such as by using
histone deacetylase inhibitors, may be therapeutically useful in promoting cell death in
neuroblastoma tumors. Since
clusterin, Bax, and Ku70 form a complex, it seemed likely that
clusterin would mediate its anti-apoptotic effects by inhibiting Ku70 acetylation and blocking Bax release. Our results, however, demonstrate that while
clusterin level does indeed determine the sensitivity of
neuroblastoma cells to
histone deacetylase inhibitor-induced cell death, it does so without affecting
histone deacetylase-inhibitor-induced Ku70 acetylation. Our results suggest that in
neuroblastoma,
clusterin exerts its anti-apoptotic effects downstream of Ku70 acetylation, likely by directly blocking Bax activation.