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RNA Interference against ATP as a Gene Therapy Approach for Prostate Cancer
Shuangya Chen1, Jisheng Ma1, Yunbei Xiao2
1School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325030, China.
Abstract:
Chemotherapeutic agents targeting energy metabolism have not achieved satisfactory results in different types of tumors. Herein, we developed an RNA interference (RNAi) method against adenosine triphosphate (ATP) by constructing an interfering plasmid-expressing ATP-binding RNA aptamer, which notably inhibited the growth of prostate cancer cells through diminishing the availability of cytoplasmic ATP and impairing the homeostasis of energy metabolism, and both glycolysis and oxidative phosphorylation were suppressed after RNAi treatment. Further identifying the mechanism underlying the effects of ATP aptamer, we surprisingly found that it markedly reduced the activity of membrane ionic channels and membrane potential which led to the dysfunction of mitochondria, such as the decrease of mitochondrial number, reduction in the respiration rate, and decline of mitochondrial membrane potential and ATP production. Meanwhile, the shortage of ATP impeded the formation of lamellipodia that are essential for the movement of cells, consequently resulting in a significant reduction of cell migration. Both the downregulation of the phosphorylation of AMP-activated protein kinase (AMPK) and endoplasmic reticulum kinase (ERK) and diminishing of lamellipodium formation led to cell apoptosis as well as the inhibition of angiogenesis and invasion. In conclusion, as the first RNAi modality targeting the blocking of ATP consumption, the present method can disturb the respiratory chain and ATP pool, which provides a novel regime for tumor therapies..
Insights
This study introduces a novel RNA interference (RNAi) therapy targeting adenosine triphosphate (ATP) to inhibit prostate cancer growth. The method disrupts cellular energy, leading to cancer cell death and reduced migration.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Chemotherapies targeting tumor energy metabolism have limited efficacy.
- Adenosine triphosphate (ATP) is crucial for cellular energy and tumor growth.
Purpose of the Study:
- To develop and evaluate an RNA interference (RNAi) strategy targeting ATP production for cancer therapy.
- To investigate the mechanism by which ATP depletion affects prostate cancer cells.
Main Methods:
- Constructed an interfering plasmid expressing an ATP-binding RNA aptamer for RNAi.
- Assessed the impact of RNAi on cellular ATP levels, energy metabolism (glycolysis, oxidative phosphorylation), mitochondrial function, and cell migration in prostate cancer cells.
- Analyzed downstream signaling pathways including AMPK and ERK phosphorylation, lamellipodium formation, apoptosis, angiogenesis, and invasion.
Main Results:
- The RNAi targeting ATP significantly inhibited prostate cancer cell growth by reducing cytoplasmic ATP availability and impairing energy metabolism.
- Suppressed both glycolysis and oxidative phosphorylation.
- Disrupted mitochondrial function, decreasing mitochondrial number, respiration rate, and membrane potential.
- Inhibited cell migration by impeding lamellipodium formation.
- Downregulated AMPK and ERK phosphorylation, promoting apoptosis and inhibiting angiogenesis and invasion.
Conclusions:
- The developed RNAi modality is the first to target and block ATP consumption, offering a novel approach for tumor therapy.
- This method effectively disturbs the cellular respiratory chain and ATP pool, presenting a new therapeutic strategy for various cancers.
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