Related Experiment Video
Updated: Jun 29, 2026
Repression of Multiple Myeloma Cell Growth In Vivo by Single-wall Carbon Nanotube (SWCNT)-delivered MALAT1 Antisense Oligos
Published on: December 13, 2018
SLC30A9-mediated mitochondrial zinc homeostasis drives osteosarcoma chemoresistance by suppressing the
Hongyu Li1, Biao Yang1, Yinliang Liu1
1Department of Orthopedics, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, China.
Aims:
To investigate the role of mitochondrial zinc (Zn) homeostasis in chemoresistance of osteosarcoma.
Material And Methods:
Zinc levels were measured in osteosarcoma cells treated with methotrexate (MTX). The expression of SLC30A9 was analyzed in chemoresistant cells. SLC30A9 knockdown and overexpression osteosarcoma cell lines were constructed for functional studies, assessing mitochondrial zinc levels, mitochondrial function, and MTX sensitivity. Subcellular localization of SLC30A9 and its zinc efflux function were determined by immunofluorescence staining and mitochondrial zinc detection. The opening of the mitochondrial permeability transition pore (mPTP), release of mitochondrial DNA (mtDNA), activation of the cGAS-STING pathway, NF-κB signaling, and NDRG1 transcription were analyzed. Xenograft mouse models were established to evaluate the effect of SLC30A9 knockdown combined with a STING agonist.
Key Findings:
MTX treatment elevated mitochondrial zinc levels, leading to mitochondrial dysfunction. SLC30A9 was highly expressed in chemoresistant osteosarcoma cells. Knockdown of SLC30A9 caused abnormal mitochondrial zinc accumulation, mitochondrial dysfunction, and reversed MTX resistance. SLC30A9 was localized to mitochondria and mediated zinc efflux; its loss triggered mtDNA release into the cytosol via mPTP, activating the cGAS-STING pathway, which in turn promoted NF-κB-driven transcription of the pro-apoptotic molecule NDRG1. In vivo, SLC30A9 knockdown combined with STING-agonist3 enhanced the chemotherapeutic effect of MTX.
Significance:
SLC30A9 maintains a low-zinc environment and mitochondrial integrity, thereby inhibiting mtDNA-mediated cGAS-STING pathway activation. Targeting SLC30A9 to disrupt this protective mechanism provides a novel therapeutic strategy for overcoming chemoresistance in osteosarcoma.
Insights
Mitochondrial zinc homeostasis, regulated by SLC30A9, impacts osteosarcoma chemoresistance. Disrupting SLC30A9 reverses resistance by activating the cGAS-STING pathway, offering a new therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Osteosarcoma exhibits chemoresistance, a major clinical challenge.
- Mitochondrial function and metal ion homeostasis are implicated in cancer progression and drug response.
Purpose of the Study:
- To investigate the role of mitochondrial zinc homeostasis in osteosarcoma chemoresistance.
- To explore SLC30A9 as a potential therapeutic target for overcoming methotrexate resistance.
Main Methods:
- Analysis of zinc levels and SLC30A9 expression in osteosarcoma cells.
- Functional studies using SLC30A9 knockdown/overexpression cell lines.
- Investigation of mitochondrial function, mtDNA release, and signaling pathways (cGAS-STING, NF-κB).
- Evaluation in xenograft mouse models.
Main Results:
- Methotrexate treatment increased mitochondrial zinc, causing dysfunction.
- SLC30A9 knockdown reversed methotrexate resistance by restoring mitochondrial integrity and inhibiting the cGAS-STING pathway.
- SLC30A9 mediates mitochondrial zinc efflux, and its loss triggers mtDNA release and NDRG1 transcription.
Conclusions:
- SLC30A9 is crucial for maintaining mitochondrial integrity and suppressing chemoresistance in osteosarcoma.
- Targeting SLC30A9 and the cGAS-STING pathway presents a novel strategy to enhance chemotherapy efficacy.
Related Concept Videos
02:23Abnormal Proliferation
03:03mTOR Signaling and Cancer Progression
The mTOR pathway or the...