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

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. 32 samples were analyzed.  10 WT, 11 transgenic, 11 KO. Totally 32 samples from C57BL/6J mice strain were used for this study. 10 wild type (WT) mice of strain, C57BL/6J, 11 separate primary tumors from 11 mice deficient in apoA-I (A-I KO) and 11 primary tumors from 11 mice expressing human apoA-I (A-I Tg+/-) were used for this study. B16F10L melanoma homograft grown in C57BL/6 mice deficient in apoA-I (A-I KO) or expressing human apoA-I (A-I Tg+/-) were resected 7 days after inoculation and processed for RNA, microarray and data analysis.