A High Dose of Calcitriol Inhibits Glycolysis and M2 Macrophage Polarization in the Tumor Microenvironment by Repressing mTOR Activation: in vitro and Molecular Docking Studies

Maliha Tabassum Munir, Sobia Ahsan Halim, Julianna Maria Santos, Faizullah Khan, Ajmal Khan, Md Mizanur Rahman, Fazle Hussain, Ahmed Al-Harrasi, Lauren S. Gollahon, Shaikh Mizanoor Rahman

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


BACKGROUND/AIMS: Macrophages interact with tumor cells within the tumor microenvironment (TME), which plays a crucial role in tumor progression. Cancer cells also can instruct macrophages to facilitate the spread of cancer and the growth of tumors. Thus, modulating macrophages-cancer cells interaction in the TME may be therapeutically beneficial. Although calcitriol (an active form of vitamin D) has anticancer properties, its role in TME is unclear. This study examined the role of calcitriol in the regulation of macrophages and cancer cells in the TME and its influence on the proliferation of breast cancer cells. METHODS: We modeled the TME, in vitro, by collecting conditioned medium from cancer cells (CCM) and macrophages (MCM) and culturing each cell type separately with and without (control) a high-dose (0.5 µM) calcitriol (an active form of vitamin D). An MTT assay was used to examine cell viability. Apoptosis was detected using FITC (fluorescein isothiocyanate) annexin V apoptosis detection kit. Western blotting was used to separate and identify proteins. Quantitative real-time PCR was used to analyze gene expression. Molecular docking studies were performed to evaluate the binding type and interactions of calcitriol to the GLUT1 and mTORC1 ligand-binding sites. RESULTS: Calcitriol treatment suppressed the expression of genes and proteins implicated in glycolysis (GLUT1, HKII, LDHA), promoted cancer cell apoptosis, and reduced viability and Cyclin D1gene expression in MCM-induced breast cancer cells. Additionally, calcitriol treatment suppressed mTOR activation in MCM-induced breast cancer cells. Molecular docking studies further showed efficient binding of calcitriol with GLUT1 and mTORC1. Calcitriol also inhibited CCM-mediated induction of CD206 and increased TNFα gene expression in THP1-derived macrophages. CONCLUSION: The results suggest that calcitriol may impact breast cancer progression by inhibiting glycolysis and M2 macrophage polarization via regulating mTOR activation in the TME and warrants further investigation in vivo.

Original languageEnglish (US)
Pages (from-to)105-122
Number of pages18
JournalCellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology
Issue number2
StatePublished - Apr 12 2023


  • Calcitriol; Tumor microenvironment; Macrophage polarization; Glycolysis; Apoptosis
  • Breast Neoplasms/pathology
  • Humans
  • Macrophages/metabolism
  • Mechanistic Target of Rapamycin Complex 1/metabolism
  • Glucose Transporter Type 1/genetics
  • Macrophage Activation
  • Glycolysis
  • Cell Line, Tumor
  • Female
  • Cell Proliferation/genetics
  • Molecular Docking Simulation
  • Tumor Microenvironment/genetics
  • Calcitriol/pharmacology
  • TOR Serine-Threonine Kinases/metabolism

ASJC Scopus subject areas

  • Medicine(all)


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