title: The JNK Signaling Pathway Is a Novel Molecular Target for S-Propargyl- L-Cysteine, a Naturally-Occurring Garlic Derivatives: Link to Its Anticancer Activity in Pancreatic Cancer In Vitro and In Vivo.
abstract: Pancreatic ductal adenocarcinoma (PDA) remains a devastating disease worldwide. Although significant improvement has been made in understanding its pathophysiology, only small portion of patients with PDA are likely to benefit from curative surgery and current chemotherapy. Thus, there is an urgent need for developing novel effective therapeutic approaches to the treatment of PDA. Today, garlic products have become an important source of effective compounds for the treatment of cancer. We have recently identified a novel garlic active component, S-propargyl-L-cysteine (SPRC), an analogue of S-Allyl Cysteine (SAC). Although its anticancer activity has been shown against several cancers, the mechanism of action is not fully understood. The present study was first designed to determine the anticancer activity of SPRC in PDA and the underlying mechanisms of action in vitro and in vivo. Our results demonstrated that SPRC reduced cell viability and colony formation, inhibited cell proliferation, induced G2/M phase cell cycle arrest and apoptosis in human PDA cells with various p53 statuses (HPAC, p53 wt; Panc-1, p53 mt). Furthermore, SPRC inhibited tumor growth in Panc-1 xenograft models. We also demonstrated that SPRC achieved its anticancer effects by regulation of the JNK protein levels through increasing its phosphorylation and decreasing its polyubiquitination-mediated degradation. In conclusion, SPRC has significant anti-PDA activity and the effects do not depend on p53 status, presumably through activating the JNK signaling pathway, providing a basis for the development of this compound as a novel target anticancer therapeutic agent for PDA.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Jianwen
authors.initials: J
authors.lastname: Cheng
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, China. zhuyz@fudan.edu.cn.
authors.forename: Yizhun
authors.initials: Y
authors.lastname: Zhu
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000302:isolation & purification / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003545:Cysteine / Q000031:analogs & derivatives* / Q000302:isolation & purification / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000302:isolation & purification / Q000494:pharmacology*; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D005737:Garlic / Q000737:chemistry; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D010766:Phosphorylation; D008517:Phytotherapy; D010946:Plants, Medicinal; D059748:Proteolysis; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection; D054875:Ubiquitination; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D020536:Enzyme Activators; C556437:S-propargylcysteine; D048031:JNK Mitogen-Activated Protein Kinases; D003545:Cysteine