Betulinic acid induces lysosome-dependent death in prostate cancer by targeting DDX5
Shoushi Liu1, Xiaolan Li1, Zhiping Cheng1
1Key Laboratory of Longevity and Aging-related Diseases of Chinese Ministry of Education& Center for Translational Medicine, Nanning 530021, China; Guangxi Key Laboratory of Bioactive Molecules Research and Evaluation & College of Pharmacy, Guangxi Medical University, Nanning 530021, China.
Background:
Prostate cancer (PCa) represents a leading cause of cancer-related mortality in men. Betulinic acid (BA) exhibits antitumor properties. However, its direct molecular target and mechanism in PCa remain unclear.
Purpose:
To identify BA's molecular target and elucidate its mechanism in inhibiting PCa progression.
Study Design:
In vitro and in vivo models were employed to evaluate BA's antitumor effects and underlying mechanisms.
Methods:
BA's antitumor activity was assessed in PCa cell lines and xenograft models. Apoptosis was examined via Hoechst staining, flow cytometry, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay. Lysosomal membrane permeabilization (LMP) was examined via LysoTracker Red and acridine orange (AO) staining, validated by CA074-Me. Target identification utilized pull-down assays, drug affinity responsive target stability (DARTS), molecular docking, and microscale thermophoresis (MST). Clinical data analysis and siRNA knockdown confirmed DDX5's role.
Results:
BA significantly suppressed PCa growth in vitro and in vivo without toxicity. BA directly bound DDX5, inhibiting transcription factor EB (TFEB)-mediated lysosomal biogenesis and downregulating V-ATPase subunit H (ATP6V1H), essential for lysosomal acidification. This disruption induced LMP and lysosome-dependent cell death (LDCD) via apoptosis, confirmed by CA074-Me. DDX5 expression was decreased in PCa tissues. DDX5 knockdown abolished BA-induced LDCD and lysosomal dysfunction.
Conclusion:
BA directly targets DDX5, inducing LDCD through the novel BA-DDX5-TFEB-ATP6V1H axis, exploiting lysosomal vulnerability in PCa. These findings underscore BA's therapeutic potential and propose lysosomal membrane destabilization as a precision treatment strategy for PCa.
Insights
Betulinic acid targets DDX5 in prostate cancer, disrupting lysosomal function and inducing cell death. This discovery offers a new therapeutic strategy by exploiting cancer cell lysosomal vulnerability.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Prostate cancer (PCa) is a major cause of male cancer mortality.
- Betulinic acid (BA) shows antitumor potential, but its mechanism in PCa is unknown.
Purpose of the Study:
- Identify the molecular target of Betulinic acid (BA) in prostate cancer (PCa).
- Elucidate the mechanism by which BA inhibits PCa progression.
Main Methods:
- Utilized in vitro and in vivo models of PCa.
- Assessed BA's effects on apoptosis, lysosomal membrane permeabilization (LMP), and cell death.
- Employed biochemical and biophysical techniques for target identification, including pull-down assays, DARTS, molecular docking, and MST.
- Validated the role of DDX5 using clinical data and siRNA knockdown.
Main Results:
- BA suppressed PCa growth in vitro and in vivo without toxicity.
- BA directly binds and inhibits DDX5, disrupting TFEB-mediated lysosomal biogenesis and V-ATPase subunit H (ATP6V1H) expression.
- This leads to LMP, lysosome-dependent cell death (LDCD), and apoptosis.
- Reduced DDX5 expression in PCa tissues and DDX5 knockdown abrogated BA's effects.
Conclusions:
- BA targets DDX5, inducing LDCD via the novel BA-DDX5-TFEB-ATP6V1H pathway.
- This mechanism exploits lysosomal vulnerability in PCa.
- Findings support BA's therapeutic potential and lysosomal membrane destabilization as a PCa treatment strategy.
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