FUNCTIONS OF APOLIPOPROTEINS IN CANCER APOPTOSIS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Cancer cells frequently possess defects in the genetic and biochemical pathways of programmed cell death (PCD). Members of the Bcl-2 family play pivotal roles regulating two types of PCD in mammals: apoptosis and autophagy. It is evident that the BH3 domain-only members of the Bcl-2 family regulate di- and or oligo-merization of the Bcl-2 family members through protein-protein interaction and therefore induce apoptosis. However, the role of the BH3 domain-only proteins in autophagic cell death has not been fully explored. 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 two novel BH3-only proteins, apolipoprotein L6 (ApoL6) and ApoL1. Previously we showed that overexpression of wild-type ApoL6 induced mitochondria-mediated apoptosis in DLD-1 cells as characterized by release of cytochrome c and Smac/DIABLO from mitochondria and activation of caspase 9, whereas ApoL6 BH3 domain deletion allele did not. Surprisingly, our recent results showed that ApoL1, a closely related protein of ApoL6, induced autophagic, rather than apoptotic, cell death in cancer cells as characterized by activation and translocation of LC3, and formation of vacuoles/autophagosomes. Inhibitors of autophagy block ApoL1-induced cell death. To our knowledge, this is the first example that intracellular overproduction of an apolipoprotein (ApoL1), which possesses a BH3-only domain, induces autophagic cell death. In addition, to explore genomic structure and functional motifs of ApoL1 and ApoL6, we have continued using biocomputing strategy to analyze exon-intron boundaries (DNA), transcript variants (RNA), protein isoforms and protein motifs/domains of ApoL1 and ApoL6. Furthermore, we have expanded this project to study the genomic structure and functional motifs of ApoL2 and ApoL3, two other members of ApoLs, which could potentially play important roles in cancer cell death.