Cambogin induces caspase-independent apoptosis through the ROS/JNK pathway and epigenetic regulation in breast cancer cells

Kaikai Shen, Jianling Xie, Hua Wang, Hong Zhang, Mengyuan Yu, Fangfang Lu, Hongsheng Tan, Hongxi Xu

Research output: Contribution to journalArticlepeer-review

25 Citations (Scopus)

Abstract

Cambogin is a polycyclic polyprenylated acylphoroglucinol (PPAP) from the Garcinia genus, which has been used traditionally for cancer treatment across Southeastern Asia. In this study, we found that cambogin inhibited breast cancer cell proliferation and induced cell apoptosis in vitro. Cambogin induced the activation of the caspase-independent mitochondrial apoptotic pathway, as indicated by an increase in the ratio of Bax/Bcl-2 and the nuclear translocation of apoptosis inducing factor (AIF). Two-dimensional gel electrophoresis and mass spectrometry revealed that the expression of proteins involving in the radical oxygen species (ROS) pathway was among the most affected upon cambogin treatment. Cambogin enhanced cellular ROS production, and induced the activation of the ASK1-MKK4/MKK7-JNK/SAPK signaling pathway. Pretreatment with ROS scavenger N-acetylcysteine (NAC), an antioxidant, or the JNK inhibitor SP600125 was able to restore cell viability in the presence of cambogin. Importantly, cambogin treatment led to the activation of activating transcription factor-2 (ATF-2) and the trimethylation of histone H3K9 in the activator protein 1 (AP-1) binding region of the Bcl-2 gene promoter. Finally, cambogin exhibited a potential antitumor effect in MCF-7 breast cancer xenografts without apparent toxicity. Taken in conjunction, the present study indicates that cambogin can induce breast adenocarcinoma cell apoptosis and therefore represents therapeutic potential for cancer treatment.

Original languageEnglish
Pages (from-to)1738-1749
Number of pages12
JournalMOLECULAR CANCER THERAPEUTICS
Volume14
Issue number7
DOIs
Publication statusPublished - 1 Jul 2015
Externally publishedYes

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