Natural lignan justicidin A-induced mitophagy as a targetable niche in bladder cancer

Area of Science:

• Mitochondrial biology
• Cancer research
• Autophagy

Background:

• Accumulated dysfunctional mitochondria contribute to cancer development.
• Mitophagy, the selective degradation of mitochondria, is hypothesized to have tumor-suppressive functions.
• Identifying natural compounds that induce mitophagy is crucial for cancer therapy.

Purpose of the Study:

• To investigate lignan justicidin A (JA) as a potential mitophagy inducer.
• To elucidate the role of JA-induced mitophagy in HRAS-mutant bladder cancer.
• To explore the therapeutic potential of JA in combination with chemotherapy.

Main Methods:

• Bioinformatics analysis to identify JA as a mitophagy inducer.
• Cell-based assays using HRAS-mutant T24 and wild-type E7 bladder cancer cells.
• Confocal and electron microscopy to visualize mitophagy markers (LC3, HSP60, BNIP3).
• Analysis of gene expression (HIF-1α, BNIP3) and protein interactions.
• Patient data analysis of mitophagy in bladder urothelial carcinoma.

Main Results:

• JA reduced T24 cell growth, altered mitochondrial membrane potential, and induced autophagy.
• JA treatment led to reduced mitochondrial puncta and co-localization of LC3 with HSP60 in autophagic vesicles, confirming mitophagy.
• JA increased HIF-1α and BNIP3 expression, with BNIP3 mediating mitophagy in HRAS-mutant cells.
• JA enhanced the cytotoxicity of cisplatin and gemcitabine in T24 cells.
• Lowered mitophagy in bladder cancer tissues and reduced mitochondrial gene expression in cisplatin-resistant cells suggest a tumor-suppressive role.

Conclusions:

• JA is a potent inducer of BNIP3-mediated mitophagy in HRAS-mutant bladder cancer cells.
• Mitophagy acts as a tumor suppressor in bladder cancer, potentially by sensitizing cells to chemotherapy and overcoming resistance.
• JA represents a promising therapeutic agent for bladder cancer, particularly in combination with standard chemotherapeutics.