Previously, we reported
apolipoprotein A-I (
apoA-I), the major
protein component of
high-density lipoprotein (HDL), has potent anti-
melanoma activity. 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 upregulated and 105 downregulated in A-I Tg+/- versus 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, along with a number of key genes in the
sterol synthesis arm of the
mevalonate pathway.
Phosphoglycerate dehydrogenase (Phgdh), the first
enzyme branching off glycolysis into the de novo
serine synthesis pathway, was the most repressed transcript in
tumors from A-I Tg+/-. We validated our mouse
tumor studies by comparing the significant transcripts with adverse
tumor markers previously identified in human
melanoma and found 45% concordance. Our findings suggest
apoA-I targets the
mevalonate and
serine synthesis pathways in
melanoma cells in vivo, thus providing anti-
tumor metabolic effects by inhibiting the flux of biomolecular building blocks for macromolecule synthesis that drive rapid
tumor growth.