{"doi":"10.18632/oncotarget.27590","title":"Apolipoprotein A-I anti-tumor activity targets cancer cell metabolism","abstract":"// Maryam Zamanian-Daryoush 1 , Daniel J. Lindner 2 , Jennifer Buffa 1 , Banu Gopalan 3 , Jie Na 4 , Stanley L. Hazen 1 , 5 and Joseph A. DiDonato 1 1 Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA 2 Taussig Cancer Institute, Cleveland Clinic, Cleveland Clinic, Cleveland, OH 44195, USA 3 Yorg Corporation, Plano, TX 75093, USA 4 Department of Health Science Research, Mayo Clinic, Rochester, MN 55905, USA 5 Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic, Cleveland, OH 44195, USA Correspondence to: Joseph A. DiDonato, email: didonaj@ccf.org Keywords: cancer; apolipoprotein A-I; cholesterol; mevalonate pathway; de novo serine synthesis pathway Received: December 07, 2019     Accepted: April 10, 2020     Published: May 12, 2020 ABSTRACT 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.","journal":"Oncotarget","year":2020,"id":106309,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":7,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9621,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":323647,"name":"Daniel J. Lindner","orcid":"0000-0002-8296-7703","position":1,"is_corresponding":false},{"id":346396,"name":"Jennifer A. Buffa","orcid":null,"position":2,"is_corresponding":false},{"id":514032,"name":"Banu Gopalan","orcid":null,"position":3,"is_corresponding":false},{"id":275168,"name":"Jie Na","orcid":"0000-0003-1820-0548","position":4,"is_corresponding":false},{"id":108895,"name":"Stanley L. Hazen","orcid":"0000-0001-7124-6639","position":5,"is_corresponding":false},{"id":108894,"name":"Joseph A. DiDonato","orcid":"0000-0002-1641-1758","position":6,"is_corresponding":false},{"id":405939,"name":"Maryam Zamanian-Daryoush","orcid":null,"position":0,"is_corresponding":true}],"reference_count":83,"raw_metadata":null,"created_at":"2026-07-18T23:12:27.124515Z","pmid":"32477466","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}