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Updated: Oct 6, 2025
Author Spotlight: Transmitochondrial Cybrid Generation Using Cancer Cell Lines
Published on: March 17, 2023
Targeted disruption of mitochondria potently reverses multidrug resistance in cancer therapy
Dingkang Liu1, Haibo Rong2, Ye Chen1
1Jiangsu Key Laboratory of Druggability of Biopharmaceuticals and State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China.
Background And Purpose:
Multidrug resistance (MDR) is a major obstacle to the successful treatment of cancer. Ample evidence shows that ATP-binding cassette (ABC) transporters and high-energy states in cells are linked to cancer drug resistance. Our previous work reported an engineered therapeutic protein named PAK, which selectively inhibited tumour progression by targeting mitochondria.
Experimental Approach:
We studied the effects of PAK on reversing drug resistance in MDR phenotypic cells and xenograft mouse models. Effects of PAK on the process of mitochondrial energy production, ABC transporter expression, and drugs enrichment were investigated in cancer cells. RNA-seq and co-immunoprecipitation were employed to analyse the mechanism of PAK on the redistribution of ABC transporters.
Key Results:
PAK promoted the enrichment of drugs in MDR cancer cells, thus enhancing the sensitivity of cancer cells to chemotherapy. Furthermore, PAK was colocalized in the mitochondria and initiated mitochondrial injury by selectively inhibiting the mitochondrial complex V. Also, ABCB1 and ABCC1 were redistributed from the plasma membrane to the cytoplasm through the disruption of lipid rafts, which was attributed to the low energy state and decreased cholesterol levels.
Conclusions And Implications:
Our results revealed a previously unrecognized pattern of reversal of drug resistance and have suggested mitochondria as a clinically relevant target for the treatment of MDR malignant tumours.
Insights
A novel therapeutic protein, PAK, reverses multidrug resistance (MDR) in cancer by targeting mitochondria. This enhances chemotherapy effectiveness by increasing drug accumulation and disrupting ATP-binding cassette transporters.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Multidrug resistance (MDR) is a significant challenge in cancer therapy.
- ATP-binding cassette (ABC) transporters and cellular energy levels are implicated in MDR.
- Previous research introduced PAK, a therapeutic protein targeting mitochondria to inhibit tumor progression.
Purpose of the Study:
- To investigate PAK's efficacy in overcoming MDR in cancer cells and in vivo models.
- To analyze PAK's impact on mitochondrial energy production and ABC transporter expression.
- To elucidate the mechanism by which PAK affects ABC transporter localization.
Main Methods:
- In vitro studies on MDR cancer cells and xenograft mouse models.
- Analysis of mitochondrial energy production and ABC transporter expression.
- RNA-sequencing and co-immunoprecipitation to study ABC transporter redistribution.
Main Results:
- PAK enhanced drug accumulation in MDR cancer cells, increasing chemosensitivity.
- PAK localized to mitochondria, inhibiting mitochondrial complex V and causing injury.
- ABCB1 and ABCC1 transporters redistributed from the plasma membrane to the cytoplasm due to lipid raft disruption, low energy, and reduced cholesterol.
Conclusions:
- Mitochondria represent a viable therapeutic target for reversing MDR in malignant tumors.
- PAK demonstrates a novel mechanism for overcoming drug resistance.
- Targeting mitochondrial function offers a new strategy for treating drug-resistant cancers.
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