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.
Highlights
Prostate cancer (PCa) is the most commonly diagnosed, noncutaneous malignancy, and the second leading cause of cancer death, in males in the United States
Lovastatin significantly enhanced in vivo antitumor efficacy of oncolytic PRRA AdE4 and AdE4-TNF-related apoptosis-inducing ligand (TRAIL)
The adenoviral vector was used to deliver a series of therapeutic genes such as HSV-TK [6], TRAIL [7], FasL [8] and endostatin-angiostatin fusion genes [9] by www.impactjournals.com/oncotarget replacing EGFP gene with therapeutic genes (Figure 1A) to improve antitumor efficacy
Summary
Prostate cancer (PCa) is the most commonly diagnosed, noncutaneous malignancy, and the second leading cause of cancer death, in males in the United States. 233,000 new diagnoses and 29,480 deaths are predicted to occur in 2014 [1]. Patients frequently exhibit locally advanced disease and/or detectable distant bone metastases at initial presentation. Androgen ablation remains the main treatment modality recommended for patients with advanced disease, with an emerging role for chemotherapy. PCa inevitably progresses to an androgen-independent (AI) lethal phenotype over time. No curative therapy is available to treat PCa after it becomes www.impactjournals.com/oncotarget hormone refractory and metastasizes to bone. At this point, the disease becomes fatal
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