Lovastatin enhances adenovirus-mediated TRAIL induced apoptosis by depleting cholesterol of lipid rafts and affecting CAR and death receptor expression of prostate cancer cells
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Youhong Liu1,*, Lin Chen1,*, Zhicheng Gong2, Liangfang Shen3, Chinghai Kao4, Janet M. Hock5, Lunquan Sun1 and Xiong Li1,6
1 Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, China
2 Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, Hunan, China
3 Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, China
4 Department of Urology, Indiana University School of Medicine, Indianapolis, IN, USA
5 The Polis Center, Indiana University and Purdue University at Indianapolis, Indianapolis, IN, USA
6 Department of Integrated Traditional Chinese and Western Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, China
* These authors contributed equally to this work
Xiong Li, email:
Keywords: Statins, Adenovirus, Gene Therapy, TRAIL, Apoptosis
Received: June 25, 2014 Accepted: December 17, 2014 Published: December 26, 2014
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.
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