Abstract 6831: Systems biology analysis of vitamin D3 reveals new anticancer properties

Abstract Introduction: Vitamin D3 (also known as cholecalciferol) is an essential nutrient and hormone that is obtained through both sunlight-mediated cutaneous synthesis and direct dietary intake. Vitamin D3 functions to inhibit tumor cell growth by arresting the cell cycle at G0/G1 phases, increasing apoptosis, and reducing nuclear β-catenin levels to prevent the formation of cancer-promoting T-cell factor complexes. This study identified the cancer cell lines most responsive to in vitro treatment with vitamin D3, as well as the compounds and genetic perturbations that are most similar to treatment with vitamin D3. Methods: For cell line response analyses, the NCI60 dataset from the US National Cancer Institute was used. Human cancer cell lines were incubated for 24 hours and treated with cholecalciferol for 48 hours at 5 different ten-fold serial dilution concentrations. Sulforhodamine B was used to measure cell survival. To identify genetic and compound perturbations similar to vitamin D3, data was obtained from the L1000 gene expression assay and CLUE. In this assay, mRNA transcript abundance was measured in 978 human landmark genes and inferred for over 11, 000 others to compare gene expression levels to those induced by vitamin D3. Results: The least sensitive cell line to vitamin D3 was the multiple myeloma cell line RPMI-8226 (IC50=56.3 µM), and the most sensitive was the colorectal cancer cell line HCT-116 (IC50 = 18.2 µM). Overall, vitamin D3 was most potent against lymphoid, renal, and melanoma cancer cell lines, and least potent against myeloma cell lines. As indicated by high median tau scores, administration of vitamin D3 induced gene expression changes similar to OTX2 and ZNF114 knockdowns; OTX2 is a transcription factor associated with neurological organ development while ZNF114 is a zinc-finger protein important for transcription regulation, and both have a biological network connection to vitamin D3. Vitamin D3 treatment has similar genetic effects to known therapeutic compounds like VX-702, nelfinavir, and calcipotriol. Conclusions: This study provides a comprehensive in vitro examination of the cancer cell lines most impacted by treatment with vitamin D3. Further research will help better inform the use of vitamin D3 in nutrition plans and guide its use in cancer prevention and treatment. Citation Format: Ashiana M. Sunderji, Shivangi Roy, Adin Aggarwal, Kenneth W. Yip. Systems biology analysis of vitamin D3 reveals new anticancer properties [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6831.