title: Clitocine potentiates TRAIL-mediated apoptosis in human colon cancer cells by promoting Mcl-1 degradation.
abstract: Among anti-cancer candidate drugs, TRAIL might be the most specific agent against cancer cells due to its low toxicity to normal cells. Unfortunately, cancer cells usually develop drug resistance to TRAIL, which is a major obstacle for its clinical application. One promising strategy is co-administrating with sensitizer to overcome cancer cells resistance to TRAIL. Clitocine, a natural amino nucleoside purified from wild mushroom, is recently demonstrated that can induce apoptosis in multidrug-resistant human cancer cells by targeting Mcl-1. In the present study,we found that pretreatment with clitocine dramatically enhances TRAIL lethality in its resistant human colon cancer cells by inducing apoptosis. More importantly, combination of clitocine and TRAIL also effectively inhibits xenograft growth and induces tumor cells apoptosis in athymic mice. The disruption of the binding between Mcl-1 and Bak as well as mitochondrial translocation of Bax mediated by clitocine are identified as the key underlying mechanisms, which leading to mitochondrial membrane permeabilization. Enforced exogenous Mcl-1 can effectively attenuate clitocine/TRAIL-induced apoptosis by suppressing the activation of intrinsic apoptotic pathway. Furthermore, clitocine regulates Mcl-1 expression at the posttranslational level as no obvious change is observed on mRNA level and proteasome inhibitor MG132 almost blocks the Mcl-1 suppression by clitocine. In fact, more ubiquitinated Mcl-1 was detected under clitocine treatment. Our findings indicate that clitocine is potentially an effective adjuvant agent in TRAIL-based cancer therapy.
authors.affiliation: Zhejiang University, Research Centre of Siyuan Natural Pharmacy and Biotoxicology, College of Life Sciences, Zijinggang Campus, Hangzhou, 310058, People's Republic of China.|Zhejiang University, Joint Centre of Zhejiang University and The Chinese University of Hong Kong on Natural Products and Toxicology Research, Zijinggang Campus, Hangzhou, People's Republic of China.
authors.forename: Jian-Guo
authors.initials: JG
authors.lastname: Sun
authors.affiliation: The Second Affiliated Hospital, Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, People's Republic of China.
authors.forename: Feng
authors.initials: F
authors.lastname: Ruan
authors.affiliation: Zhejiang University, Research Centre of Siyuan Natural Pharmacy and Biotoxicology, College of Life Sciences, Zijinggang Campus, Hangzhou, 310058, People's Republic of China.
authors.forename: Xue-Li
authors.initials: XL
authors.lastname: Zeng
authors.affiliation: Zhejiang University, Research Centre of Siyuan Natural Pharmacy and Biotoxicology, College of Life Sciences, Zijinggang Campus, Hangzhou, 310058, People's Republic of China.
authors.forename: Jun
authors.initials: J
authors.lastname: Xiang
authors.affiliation: Zhejiang University, Research Centre of Siyuan Natural Pharmacy and Biotoxicology, College of Life Sciences, Zijinggang Campus, Hangzhou, 310058, People's Republic of China.
authors.forename: Xia
authors.initials: X
authors.lastname: Li
authors.affiliation: Zhejiang University, Research Centre of Siyuan Natural Pharmacy and Biotoxicology, College of Life Sciences, Zijinggang Campus, Hangzhou, 310058, People's Republic of China.|Zhejiang University, Joint Centre of Zhejiang University and The Chinese University of Hong Kong on Natural Products and Toxicology Research, Zijinggang Campus, Hangzhou, People's Republic of China.
authors.forename: Ping
authors.initials: P
authors.lastname: Wu
authors.affiliation: Zhejiang University, Joint Centre of Zhejiang University and The Chinese University of Hong Kong on Natural Products and Toxicology Research, Zijinggang Campus, Hangzhou, People's Republic of China.|School of Biomedical Sciences (SBS), The Chinese University of Hong Kong, Shatin, Hong Kong SAR, People's Republic of China.
authors.forename: Kwok Pui
authors.initials: KP
authors.lastname: Fung
authors.affiliation: Zhejiang University, Research Centre of Siyuan Natural Pharmacy and Biotoxicology, College of Life Sciences, Zijinggang Campus, Hangzhou, 310058, People's Republic of China. liuf64@zju.edu.cn.|Zhejiang University, Joint Centre of Zhejiang University and The Chinese University of Hong Kong on Natural Products and Toxicology Research, Zijinggang Campus, Hangzhou, People's Republic of China. liuf64@zju.edu.cn.
authors.forename: Fei-Yan
authors.initials: FY
authors.lastname: Liu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D008819:Mice, Nude; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D011741:Pyrimidine Nucleosides / Q000008:administration & dosage*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D011741:Pyrimidine Nucleosides; D053221:TNF-Related Apoptosis-Inducing Ligand; C055433:clitocine
keywords: Apoptosis; Clitocine; Human colon cancer; Mcl-1; TRAIL