期刊
ACTA PHARMACOLOGICA SINICA
卷 34, 期 9, 页码 1183-1191出版社
ACTA PHARMACOLOGICA SINICA
DOI: 10.1038/aps.2013.68
关键词
retigeric acid B; prostate cancer; reactive oxygen species (ROS); mitochondria; mitophagy; apoptosis
资金
- National Natural Science Foundation of China [81273533, 30925038]
- Natural Science Foundation of Shandong Province, China [2009ZRB01346]
Aim: Retigeric acid B (RAB), a pentacyclic triterpenic acid from Lobaria kurokawae Yoshim, has been found to induce apoptosis in prostate cancer cells. The aim of this study was to investigate the roles of mitochondrial damage-caused mitophagy in RAB-induced prostate cancer cell death in vitro. Methods: Human prostate cancer PC3 and LNCaP cells were tested. Cell viability was analyzed with MTT assay. Cell apoptosis, ROS level and mitochondrial transmembrane potential (mt Delta psi) were measured with flow cytometry. Autophagy-and apoptosis-related proteins were studied using Western blotting. GFP-LC3B puncta, mitochondrial swelling and mitophagy were examined morphologically. Quantitative RT-PCR was used to measure LC3B mRNA level, and siRNA was used to knock down LC3BII. Results: In both PC3 and LNCaP cells, RAB (15 mu mol/L) increased ROS accumulation and decreased mt Delta psi in a time-dependent manner. Furthermore, RAB induced mitochondrial swelling and mitophagy, significantly increased LC3B expression and conversion of LC3BI to LC3BII, and the elimination of mitochondria by LC3BII-containing autophagolysosomes. In addition, RAB suppressed the PI3K/Akt/mTOR pathway activation. Pretreatment of PC3 cells with autophagy inhibitor 3-MA (5 mmol/L) or the lysosomal protease inhibitor CQ (10 mu mol/L) significantly increased RAB-induced apoptosis. Similar results were obtained in RAB-treated PC3 cells with LC3B knocked down. Conclusion: RAB induces mitochondrial damage and mitophagy that attenuates RAB-induced prostate cancer cell death. Thus, suppression of mitophagy might be a potential strategy for improving the chemotherapeutic effects of RAB.
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