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: Youhong Liu, Lin Chen, Zhicheng Gong, Liangfang Shen, Chinghai Kao, Janet M Hock, Lunquan Sun, Xiong Li
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 5 Pg. 3055-70 (Feb 20 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 25605010 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antineoplastic Agents
• CLMP protein, human
• Coxsackie and Adenovirus Receptor-Like Membrane Protein
• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• Integrins
• Receptors, TNF-Related Apoptosis-Inducing Ligand
• TNF-Related Apoptosis-Inducing Ligand
• TNFRSF10A protein, human
• Cholesterol
• Lovastatin

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cholesterol (deficiency)
• Coxsackie and Adenovirus Receptor-Like Membrane Protein (drug effects, metabolism)
• Dependovirus (genetics, metabolism)
• Dose-Response Relationship, Drug
• Genetic Therapy (methods)
• Genetic Vectors
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors (pharmacology)
• Integrins (metabolism)
• Lovastatin (pharmacology)
• Male
• Membrane Microdomains (drug effects, metabolism)
• Oncolytic Virotherapy (methods)
• Prostatic Neoplasms (genetics, metabolism, pathology, therapy)
• Receptors, TNF-Related Apoptosis-Inducing Ligand (drug effects, metabolism)
• Signal Transduction (drug effects)
• TNF-Related Apoptosis-Inducing Ligand (biosynthesis, genetics)
• Time Factors
• Transduction, Genetic
• Xenograft Model Antitumor Assays