Phytomedicine : international journal of phytotherapy and phytopharmacology · 2026
Betulinic acid induces lysosome-dependent death in prostate cancer by targeting DDX5.
СтатьяНазвание и аннотация: Перевод в очереди
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Liu Shoushi, Li Xiaolan, Cheng Zhiping, Zhao Kaili, Wang Yanting, Wei Yuhe, Wang Yuanshuo, Lu Jinjian, Yang Xin, Lim Yang Mooi, Lu Qinpei, Huang Qiuju, Guo Hongwei
Аннотация
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.
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.