Apolipoprotein A-I anti-tumor activity targets cancer cell metabolism

• Published in: Oncotarget 2020-05, Vol.11 (19), p.1777-1796
• Main Authors: Zamanian-Daryoush, Maryam, Lindner, Daniel J, Buffa, Jennifer, Gopalan, Banu, Na, Jie, Hazen, Stanley L, DiDonato, Joseph A
• Format: Article
• Language: English
• Subjects: Research Paper
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.27590

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 < 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 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 ( ), 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 ( ), the first enzyme branching off glycolysis into the 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 , thus providing anti-tumor metabolic effects by inhibiting the flux of biomolecular building blocks for macromolecule synthesis that drive rapid tumor growth.