HIF-1α-Mediated Mitophagy Determines ZnO Nanoparticle-Induced Human Osteosarcoma Cell Death both In Vitro and In Vivo

ACS Appl Mater Interfaces. 2020 Oct 28;12(43):48296-48309. doi: 10.1021/acsami.0c12139. Epub 2020 Oct 15.


Although ZnO nanoparticles (NPs) can kill human osteosarcoma cells, the underlying upstream regulatory mechanisms remain unclear. Since hypoxia inducible factor-1α (HIF-1α) regulates the tumor microenvironment, here we explored the interplay between HIF-1α regulation and mitophagy in ZnO NP-induced osteosarcoma inhibition both in vivo and in vitro. We found that ZnO NPs upregulated HIF-1α protein levels when they killed four common human osteosarcoma cell lines. This finding was consistent with our observations that additional HIF-1α upregulation by a hypoxia inducer CoCl2 or under a 1% hypoxia environment enhanced NP-induced cell death, but concurrent HIF-1α suppression by a hypoxia inhibitor YC-1 or HIF-1α siRNA inhibited NP-induced cell death. We discovered an interplay between HIF-1α and the autophagy-Zn2+-reactive oxygen species (ROS)-autophagy cycle axis and revealed that NP-induced cancer cell killing followed a HIF-1α-BNIP3-LC3B-mediated mitophagy pathway. We confirmed that NP-upregulated HIF-1α protein expression was attributed to prolyl hydroxylase inhibition by both ROS and Zn2+. In addition, the in vivo assay confirmed the therapeutic effectiveness and safety of ZnO NPs on a nude mice osteosarcoma model. Collectively, our findings clarified the upstream regulatory mechanism of autophagy induced by the NPs and further demonstrated their antitumor ability in vivo. This work provides new targets and strategies for enhancing NP-based osteosarcoma treatment.

Keywords: HIF-1α; ZnO NPs; apoptosis; mitophagy; osteosarcoma.

MeSH terms

  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Bone Neoplasms / drug therapy*
  • Bone Neoplasms / metabolism
  • Bone Neoplasms / pathology
  • Cell Death / drug effects
  • Cell Proliferation / drug effects
  • Drug Screening Assays, Antitumor
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / antagonists & inhibitors
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Indazoles / pharmacology
  • Nanoparticles / chemistry*
  • Osteosarcoma / drug therapy*
  • Osteosarcoma / metabolism
  • Osteosarcoma / pathology
  • Particle Size
  • RNA, Small Interfering / pharmacology
  • Surface Properties
  • Tumor Cells, Cultured
  • Tumor Microenvironment / drug effects
  • Zinc Oxide / chemistry
  • Zinc Oxide / pharmacology*


  • Antineoplastic Agents
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Indazoles
  • RNA, Small Interfering
  • 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole
  • Zinc Oxide