title: Lovastatin enhances adenovirus-mediated TRAIL induced apoptosis by depleting cholesterol of lipid rafts and affecting CAR and death receptor expression of prostate cancer cells.
abstract: Oncolytic adenovirus and apoptosis inducer TRAIL are promising cancer therapies. Their antitumor efficacy, when used as single agents, is limited. Oncolytic adenoviruses have low infection activity, and cancer cells develop resistance to TRAIL-induced apoptosis. Here, we explored combining prostate-restricted replication competent adenovirus-mediated TRAIL (PRRA-TRAIL) with lovastatin, a commonly used cholesterol-lowering drug, as a potential therapy for advanced prostate cancer (PCa). Lovastatin significantly enhanced the efficacy of PRRA-TRAIL by promoting the in vivo tumor suppression, and the in vitro cell killing and apoptosis induction, via integration of multiple molecular mechanisms. Lovastatin enhanced PRRA replication and virus-delivered transgene expression by increasing the expression levels of CAR and integrins, which are critical for adenovirus 5 binding and internalization. Lovastatin enhanced TRAIL-induced apoptosis by increasing death receptor DR4 expression. These multiple effects of lovastatin on CAR, integrins and DR4 expression were closely associated with cholesterol-depletion in lipid rafts. These studies, for the first time, show correlations between cholesterol/lipid rafts, oncolytic adenovirus infection efficiency and the antitumor efficacy of TRAIL at the cellular level. This work enhances our understanding of the molecular mechanisms that support use of lovastatin, in combination with PRRA-TRAIL, as a candidate strategy to treat human refractory prostate cancer in the future.
authors.affiliation: Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Youhong
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Zhicheng
authors.initials: Z
authors.lastname: Gong
authors.affiliation: Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Liangfang
authors.initials: L
authors.lastname: Shen
authors.affiliation: Department of Urology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Chinghai
authors.initials: C
authors.lastname: Kao
authors.affiliation: The Polis Center, Indiana University and Purdue University at Indianapolis, Indianapolis, IN, USA.
authors.forename: Janet M
authors.initials: JM
authors.lastname: Hock
authors.affiliation: Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Lunquan
authors.initials: L
authors.lastname: Sun
authors.affiliation: Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, China.|Department of Integrated Traditional Chinese and Western Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, China.
authors.forename: Xiong
authors.initials: X
authors.lastname: Li
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000172:deficiency*; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein / Q000187:drug effects* / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D016023:Integrins / Q000378:metabolism; D008148:Lovastatin / Q000494:pharmacology*; D008297:Male; D021962:Membrane Microdomains / Q000187:drug effects* / Q000378:metabolism; D050130:Oncolytic Virotherapy / Q000379:methods*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000096:biosynthesis* / Q000235:genetics; D013997:Time Factors; D014161:Transduction, Genetic; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C568771:CLMP protein, human; D062727:Coxsackie and Adenovirus Receptor-Like Membrane Protein; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D016023:Integrins; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; D002784:Cholesterol; D008148:Lovastatin