title: Piperlongumine selectively kills hepatocellular carcinoma cells and preferentially inhibits their invasion via ROS-ER-MAPKs-CHOP.
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 IC50 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.
authors: 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.
authors: Yong
authors: Y
authors: Chen
authors: 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.
authors: Ju Mei
authors: JM
authors: Liu
authors: 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.
authors: Xin Xin
authors: XX
authors: Xiong
authors: 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.
authors: Xin Yao
authors: XY
authors: Qiu
authors: Department of Urology, Union Hospital, Huazhong University of Science and Technology, Wuhan, China.
authors: Feng
authors: F
authors: Pan
authors: Department of Urology, Union Hospital, Huazhong University of Science and Technology, Wuhan, China.
authors: Di
authors: D
authors: Liu
authors: Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors: Shu Jue
authors: SJ
authors: Lan
authors: Department of Pharmacology, School of Basic Medicine, Huazhong University of Science and Technology, Wuhan, China.
authors: Si
authors: S
authors: Jin
authors: 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.
authors: Shang Bin
authors: SB
authors: Yu
authors: 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.
authors: Xiao Qian
authors: XQ
authors: Chen
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004148:Dioxolanes / Q000494:pharmacology*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism*; D051742:Transcription Factor CHOP / Q000378:metabolism*; D014162:Transfection; D010881:Piperidones
chemical_list: D004148:Dioxolanes; D000091342:Endoplasmic Reticulum Chaperone BiP; D017382:Reactive Oxygen Species; D051742:Transcription Factor CHOP; C000717248:Hspa5 protein, mouse; C498077:piperlongumine; D010881:Piperidones
keywords: chemotherapy; hepatocellular carcinoma; oxidative stress; piperlongumine; signaling pathway