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Apolipoprotein A-I Anti-tumor Activity Targets Cancer Cell Metabolism

ABSTRACT: Previously, we reported apolipoprotein A-I (apoA-I), the major protein component of high-density lipoprotein (HDL) has potent anti-melanoma activity. Herein, we used DNA microarray and bioinformatics to interrogate gene expression profiles of tumors from apoA-I expressing (A-I Tg+/-) versus apoA-I-null (A-I KO) animals to gain insights into mechanisms of apoA-I tumor protection. Differential expression analyses of 11 distinct tumors per group with > 1.2-fold cut off and a false discovery rate adjusted p< 0.05, identified 176 significant transcripts (71 up- and 105 down-regulated in A-I Tg+/- relative to A-I KO group). Bioinformatic analyses identified the mevalonate and de novo serine/glycine synthesis pathways as potential targets for apoA-I anti-tumor activity. Relative to A-I KO, day-7 B16F10L melanoma tumor homografts from A-I Tg+/- exhibited reduced expression of mevalonate-5-pyrophosphate decarboxylase (MVD), a key enzyme targeted in cancer therapy, as well as squalene epoxidase (Sqle), cytochrome P450, family 51 (Cyp51), hydroxysteroid (17-beta) dehydrogenase 7 (Hsd17b7), and 24-dehydrocholesterol reductase (Dhcr24) with the latter four serving in the sterol synthesis arm of the mevalonate pathway. Phosphoglycerate dehydrogenase (Phgdh), the first enzyme branching off glycolysis in de novo serine synthesis pathway was the most repressed transcript in tumors from A-I Tg+/-. We validated the experimental approach by correlating gene expression patterns in a mouse model where A-I KO is tumor-permissive relative to A-I Tg+/-, with adverse tumor markers previously identified in human melanoma and found 45% concordance. We propose that apoA-I, a physiological serum protein may target the mevalonate and serine synthesis pathways in melanoma cells, in vivo, thus inhibiting the flux of building blocks for macromolecule synthesis that drive rapid tumor growth.

ORGANISM(S): Mus musculus

PROVIDER: GSE137532 | GEO | 2020/06/04

REPOSITORIES: GEO

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Project description:D-3-Phosphoglycerate dehydrogenase (Phgdh; EC 1.1.1.95) is a necessary enzyme for de novo L-serine biosynthesis via the phosphorylated pathway. We demonstrated previously that Phgdh is expressed exclusively by neuroepithelium and radial glia in developing mouse brain and later mainly by astrocytes. Mutations in the human PHGDH gene cause serine deficiency disorders (SDD) associated with severe neurological symptoms such as congenital microcephaly, psychomotor retardation, and intractable seizures. We recently demonstrated that genetically engineered mice, in which the gene for Phgdh has been disrupted, have significantly decreased levels of serine and glycine, and exhibit malformation of brain such as microcephaly. The Phgdh null (KO) embryos exhibit lethal phenotype after gestational day 14, indicating that the phosphorylated pathway is essential for embryogenesis, especially for brain development. It is worth noting that the Phgdh knockout (KO) embryos primarily displayed microcephaly, which is the most conspicuous phenotype of patients with SDD. Thus, Phgdh KO mice are a useful animal model for studying the effect of diminished L-serine levels on development of the central nervous system and other organs. To better understand the mechanism underlying the molecular pathogenesis of SDD, we sought to examine whether gene expression is altered in the Phgdh KO mouse model. We identify genes that have altered expression in the head of the Phgdh KO embryos using the GeneChip array. Some of the genes identified by this method belong in functional categories that are relevant to the biochemical and morphological aberrations of the Phgdh deletion. Experiment Overall Design: Total RNA samples were prepared from head tissues from 2 embryos of Phgdh knockout and littermate wild-type controls. Experiment Overall Design: RNA of 4 biological replicates was hybridized to Affymetrix Mouse Genome 430 2.0 arrays. Five microgram total RNA was labelled according to the ENZO-protocol, fragmented and hybridized according to Affymetrix's protocols.

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Apolipoprotein A-I Anti-tumor Activity Targets Cancer Cell Metabolism

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