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Cytotoxic Efficacy of Photodynamic Therapy in Osteosarcoma Cells In Vitro
Published on: March 18, 2014
HIF-1α-Mediated Mitophagy Determines ZnO Nanoparticle-Induced Human Osteosarcoma Cell Death both In Vitro and In Vivo
Guanping He1, Xiaoyu Pan1, Xiao Liu1
1Department of Orthopedics, Peking University Third Hospital, No. 49, North Garden Street, Haidian District, Beijing 100191, China.
Abstract:
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.
Insights
Zinc oxide nanoparticles (ZnO NPs) kill osteosarcoma cells by upregulating hypoxia-inducible factor-1α (HIF-1α), triggering mitophagy. This clarifies mechanisms for enhanced ZnO NP cancer therapy.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Cancer Biology
Background:
- Osteosarcoma remains a significant challenge in oncology.
- Zinc oxide nanoparticles (ZnO NPs) show potential in cancer therapy.
- The precise molecular mechanisms of ZnO NP-induced cancer cell death are not fully understood.
Purpose of the Study:
- To elucidate the upstream regulatory mechanisms of ZnO NP-induced osteosarcoma cell death.
- To investigate the role of hypoxia-inducible factor-1α (HIF-1α) and mitophagy in ZnO NP treatment.
- To evaluate the in vivo therapeutic efficacy and safety of ZnO NPs.
Main Methods:
- In vitro studies using four human osteosarcoma cell lines.
- In vivo studies using a nude mice osteosarcoma model.
- Manipulation of HIF-1α levels using chemical inducers (CoCl2), inhibitors (YC-1), hypoxia, and siRNA.
- Analysis of the autophagy-Zn2+-ROS-autophagy cycle and the HIF-1α-BNIP3-LC3B mitophagy pathway.
Main Results:
- ZnO NPs significantly upregulated HIF-1α protein levels in osteosarcoma cells.
- Enhanced HIF-1α levels potentiated ZnO NP-induced cell death, while suppression inhibited it.
- A novel pathway involving HIF-1α, BNIP3, and LC3B-mediated mitophagy was identified.
- ROS and Zn2+ inhibited prolyl hydroxylase, leading to NP-upregulated HIF-1α.
- In vivo studies confirmed ZnO NPs' therapeutic effectiveness and safety in an osteosarcoma model.
Conclusions:
- ZnO NPs induce osteosarcoma cell death via a HIF-1α-mediated mitophagy pathway.
- The findings clarify the upstream regulatory mechanisms of NP-induced autophagy.
- This study provides new therapeutic targets and strategies for enhancing ZnO NP-based osteosarcoma treatment.
