Piperlongumine selectively kills hepatocellular carcinoma cells and preferentially inhibits their invasion via ROS-ER-MAPKs-CHOP.

// Yong Chen 1 , Ju Mei Liu 1 , Xin Xin Xiong 1 , Xin Yao Qiu 1 , Feng Pan 2 , Di Liu 2 , Shu Jue Lan 3 , Si Jin 4 , Shang Bin Yu 1 and Xiao Qian Chen 1 1 Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Institute of Brain Research, Key Laboratory of Neurological Diseases, Ministry of Education, Hubei Provincial Key Laboratory of Neurological Diseases, Huazhong University of Science and Technology, Wuhan, China 2 Department of Urology, Union Hospital, Huazhong University of Science and Technology, Wuhan, China 3 Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China 4 Department of Pharmacology, School of Basic Medicine, Huazhong University of Science and Technology, Wuhan, China Correspondence to: Xiao Qian Chen, email: // Keywords : piperlongumine, hepatocellular carcinoma, oxidative stress, signaling pathway, chemotherapy Received : December 21, 2014 Accepted : January 21, 2015 Published : January 31, 2015 Abstract Hepatocellular carcinomas (HCC) are highly malignant and aggressive tumors lack of effective therapeutic drugs. Piperlongumine (PL), a natural product isolated from longer pepper plants, is recently identified as a potent cytotoxic compound highly selective to cancer cells. Here, we reported that PL specifically suppressed HCC cell migration/invasion via endoplasmic reticulum (ER)-MAPKs-CHOP signaling pathway. PL selectively killed HCC cells but not normal hepatocytes with an IC 50 of 10-20 µM while PL at much lower concentrations only suppressed HCC cell migration/invasion. PL selectively elevated reactive oxygen species (ROS) in HCC cells, which activated or up-regulated downstream PERK/Ire 1α/Grp78, p38/JNK/Erk and CHOP subsequently. Administration of antioxidants completely abolished PL’s effects on cell death and migration/invasion. However, pharmacological inhibition of ER stress-responses or MAPKs signaling pathways with corresponding specific inhibitors only reversed PL’s effect on cell migration/invasion but not on cell death. Consistently, knocking-down of CHOP by RNA interference only reversed PL-suppressed HCC cell migration. Finally, PL significantly suppressed HCC development and activated the ER-MAPKs-CHOP signaling pathway in HCC xenografts in vivo . Taken together, PL selectively killed HCC cells and preferentially inhibited HCC cell migration/invasion via ROS-ER-MAPKs-CHOP axis, suggesting a novel therapeutic strategy for the highly malignant and aggressive HCC clinically.