ABSTRACT
According to recent studies, Cannabidiol (CBD), one of the main components of Cannabis sativa, has anticancer effects in several cancers. However, the exact mechanism of CBD action is not currently understood. Here, CBD promoted cell death in gastric cancer. We suggest that CBD induced apoptosis by suppressing X-linked inhibitor apoptosis (XIAP), a member of the IAP protein family. CBD reduced XIAP protein levels while increasing ubiquitination of XIAP. The expression of Smac, a known inhibitor of XIAP, was found to be elevated during CBD treatment. Moreover, CBD treatment increased the interaction between XIAP and Smac by increasing Smac release from mitochondria to the cytosol. CBD has also been shown to affect mitochondrial dysfunction. Taken together, these results suggest that CBD may have potential as a new therapeutic target in gastric cancer.
Subject(s)
Apoptosis Regulatory Proteins/metabolism , Apoptosis , Biomarkers, Tumor/metabolism , Cannabidiol/pharmacology , Gene Expression Regulation, Neoplastic/drug effects , Mitochondrial Proteins/metabolism , Stomach Neoplasms/pathology , X-Linked Inhibitor of Apoptosis Protein/metabolism , Animals , Apoptosis Regulatory Proteins/genetics , Biomarkers, Tumor/genetics , Cell Proliferation , Female , Humans , Mice , Mice, Inbred BALB C , Mice, Nude , Mitochondrial Proteins/genetics , Neoplasm Invasiveness , Stomach Neoplasms/genetics , Stomach Neoplasms/metabolism , Tumor Cells, Cultured , X-Linked Inhibitor of Apoptosis Protein/genetics , Xenograft Model Antitumor AssaysABSTRACT
15-Lipoxygenase-1 (15-LOX-1) is an inducible and highly regulated enzyme in normal human cells that plays a key role in the production of lipid signaling mediators, such as 13-hydroxyoctadecadienoic acid (13-HODE) from linoleic acid. 15-LOX-1 significantly contributes to the resolution of inflammation and to the terminal differentiation of normal cells. 15-LOX-1 is downregulated in human colorectal polyps and cancers. Emerging data support a tumor suppressor role for 15-LOX-1, especially in colon cancer. These data indicate that 15-LOX-1 promotes various anti-tumorigenic events, including cell differentiation and apoptosis, and inhibits chronic inflammation, angiogenesis, and metastasis. The transcriptional repression of 15-LOX-1 in colon cancer cells is complex and involves multiple mechanisms (e.g., histone methylation, transcriptional repressor binding). Re-expression of 15-LOX-1 in colon cancer cells can function as an important therapeutic mechanism and could be further exploited to develop novel treatment approaches for this common cancer.
