Molecular mechanism of Gd@C 82(OH) 22 increasing collagen expression: Implication for encaging tumor

Biomaterials. 2018 Jan;152:24-36. doi: 10.1016/j.biomaterials.2017.10.027. Epub 2017 Oct 16.

Abstract

Gadolinium-containing fullerenol Gd@C82(OH)22 has demonstrated low-toxicity and highly therapeutic efficacy in inhibiting tumor growth and metastasis through new strategy of encaging cancer, however, little is known about the mechanisms how this nanoparticle regulates fibroblast cells to prison (instead of poison) cancer cells. Here, we report that Gd@C82(OH)22 promote the binding activity of tumor necrosis factor (TNFα) to tumor necrosis factor receptors 2 (TNFR2), activate TNFR2/p38 MAPK signaling pathway to increase cellular collagen expression in fibrosarcoma cells and human primary lung cancer associated fibroblasts isolated from patients. We also employ molecular dynamics simulations to study the atomic-scale mechanisms that dictate how Gd@C82(OH)22 mediates interactions between TNFα and TNFRs. Our data suggest that Gd@C82(OH)22 might enhance the association between TNFα and TNFR2 through a "bridge-like" mode of interaction; by contrast, the fullerenol appears to inhibit TNFα-TNFR1 association by binding to two of the receptor's cysteine-rich domains. In concert, our results uncover a sequential, systemic process by which Gd@C82(OH)22 acts to prison tumor cells, providing new insights into principles of designs of cancer therapeutics.

Keywords: Caging cancer cells; Cancer therapeutics; Fibrosarcoma cells; Gd-metallofullerenol; Molecular dynamics; TNF receptors.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry*
  • Cell Line, Tumor
  • Collagen / metabolism*
  • Fibrosarcoma / pathology
  • Fullerenes / chemistry*
  • Gadolinium / chemistry*
  • Humans
  • Lung Neoplasms / pathology
  • Metal Nanoparticles / chemistry*
  • Mice
  • Molecular Dynamics Simulation
  • Particle Size
  • Receptors, Tumor Necrosis Factor, Type II / chemistry
  • Receptors, Tumor Necrosis Factor, Type II / metabolism
  • Surface Properties
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha / chemistry
  • Tumor Necrosis Factor-alpha / metabolism
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Antineoplastic Agents
  • Fullerenes
  • Receptors, Tumor Necrosis Factor, Type II
  • Tumor Necrosis Factor-alpha
  • fullerenol
  • Collagen
  • Gadolinium
  • p38 Mitogen-Activated Protein Kinases