ROS-mediated Autophagy Induced By Dysregulation Of Lipid Metabolism Plays A Protective Role In Colorectal Cancer Cells Treated With Gambogic Acid

Colorectal cancer (CRC) is the third leading cause of cancer and the fourth most common cause of cancer-related deaths worldwide, unfortunately, to date there are only limited effective treatment strategies for advanced CRC. Herefore, improved systemic therapeutic options are urgently required to effectively eliminate primary or metastatic cancer, for which new drug development offers promising options. Gambogic acid (GA), the main active compound of resin. Over the past half-century, pharmacological studies have revealed that GA has strong antitumor activities against various tumors including human leukemia, hepatoma, oral, breast, gastric, pancreatic, prostate, epithelial cervical and lung cancer. Recently, GA has also been reported to have a marked anti-tumor effect for CRC cells in vivo and in vitro. Due to the wide spectrum of anti-tumor activity and minimal toxicity to normal cells, GA has been approved by the Chinese Food and Drug Administration for the treatment of various cancers in clinical trials and has finished phase II clinical trials. However, the precise molecular mechanisms still remain unclear and require further exploration.In this study, we found that GA could initiate proliferative inhibition, caspase-dependent apoptotic cell death and autophagy in colorectal carcinoma cells, and inhibition of the autophagy process accelerated the effect of proliferative inhibition and apoptotic cell death induced by GA, implying a protective role of autophagy. Two-dimensional electrophoresis-based proteomics showed that GA treatment altered expression of multiple redox and lipid metabolism regulatory proteins. Functional studies revealed that GA-induced dysregulation of lipid metabolism could activate lipoxygenase (LOX), resulting in intracellular ROS accumulation, which is required for inhibition of Akt-mTOR signaling and autophagy initiation upon GA treatment. Finally, a xenograft model confirmed that GA could also cause tumor cell death and autophagy in vivo. Taken together, these data show new biological activities of GA against colorectal carcinoma underlying the protective role of ROS-induced autophagy. These results will provide valuable information for future studies to decipher the anticancer molecular mechanisms of GA in more detail.