Cancer cells frequently possess defects in the genetic and biochemical pathways of apoptosis. Members of the Bcl-2 family play pivotal roles in regulating apoptosis and possess at least one of four Bcl-2-Homology (BH) domains, designated, BH1, BH2, BH3, and BH4. The BH3 domain is the only one conserved in pro-apoptotic BH3-only proteins and plays an important role in protein-protein interactions in apoptosis by regulating homo- and hetero-dimerization of the Bcl-2 family members. To date, ten BH3-only pro-apoptotic proteins have been identified and characterized in human genome. The completion of the Human Genome Project and the availability of various public databases and sequence analysis algorithms allowed us to utilize the bioinformatic data-mining approach to identify one novel BH3-only protein, apolipoprotein L6 (ApoL6). The full-length cDNA of ApoL6 was identified, cloned and functionally expressed in p53-null colorectal cancer cells (DLD-1). We found that overexpression of wild-type ApoL6 induced mitochondria-mediated apoptosis in DLD-1 cells characterized by release of cytochrome c and Smac/DIABLO from mitochondria and activation of caspase 9 whereas ApoL6 BH3 domain deletion allele did not. In addition, overexpression of ApoL6 also induced activation of caspase 8. Furthermore, we showed that adenovirus harboring the full-length cDNA of ApoL6 induced marked apoptosis in a variety of cancer cell types, and ApoL6 recruited and interacted with lipid/fatty acid components during the induction of apoptosis. To our knowledge, this is the first example that intracellular overproduction of an apolipoprotein induces marked apoptosis.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]