Tumor suppressor in lung cancer-1 (TSLC1) mediated by dual-regulated oncolytic adenovirus exerts specific antitumor actions in a mouse model

Abstract

Aim:The tumor suppressor in lung cancer-1 (TSLC1) is a candidate tumor suppressor of lung cancer, and frequently inactivated in primary non-small cell lung cancer (NSCLC). In this study, we investigated the effects of TSLC1 mediated by a dual-regulated oncolytic adenovirus on lung cancer, and the mechanisms underlying the antitumor actions. Methods: The recombinant virus Ad·sp-E1A (∆24) -TSLC1 was constructed by inserting the TSLC1 gene into the dual-regulated Ad·sp-E1A (∆24) vector, which contained the survivin promoter and a 24 bp deletion within E1A. The antitumor effects of Ad·sp-E1A (∆24) -TSLC1 were evaluated in NCI-H460, A549, and H1299 lung cancer cell lines and the normal fibroblast cell line MRC-5, as well as in A549 xenograft model in nude mice. Cell viability was assessed using MTT assay. The expression of TSLC1 and activation of the caspase signaling pathway were detected by Western blot analyses. The tumor tissues from the xenograft models were examined using H&E staining, IHC, TUNEL, and TEM analyses. Results: Infection of A549 lung cancer cells with Ad·sp-E1A (∆24) -TSLC1 induced high level expression of TSLC1. Furthermore, the Ad·sp-E1A (∆24) -TSLC1 virus dose-dependently suppressed the viability of NCI-H460, A549, and H1299 lung cancer cells, and did not affect MRC-5 normal fibroblast cells. Infection of NCI-H460, A549, and H1299 lung cancer cells with Ad·sp-E1A (∆24) -TSLC1 induced apoptosis, and increased activation of caspase-8, caspase-3 and PARP. In A549 xenograft model in nude mice, intratumoral injection of Ad·sp-E1A (∆24) -TSLC1 significantly suppressed the tumor volume, and increased the survival rate (from less than 15% to 87.5% at d 60). Histological studies showed that injection of Ad·sp-E1A (∆24) -TSLC1 caused tumor cell apoptosis and virus particle propagation in tumor tissues. Conclusion: The oncolytic adenovirus Ad·sp-E1A (∆24) -TSLC1 exhibits specific antitumor effects, and is a promising agent for the treatment of lung cancer.

A novel Golgi protein (GOLPH2)-regulated oncolytic adenovirus exhibits potent antitumor efficacy in hepatocellular carcinoma

“…Oncolytic virus has emerged as one of the most prospective anticancer drugs because the engineered viruses can successfully tackle cancer cells without damaging normal tissue [ 15 ]. Several excellent genetically modified oncolytic virus including vaccine virus JX-594, herpes simplex virus OncoVEX-GM-CSF, adenovirus H101, and reovirus Reolysin have been successfully used to treat various cancers in clinic and obtained specific cancer-killing effect [ 14 ]. In addition, oncolytic virus can induce the immune response against the tumor through releasing antigens when virus attacked cancer cells [ 23 ].…”

“…However, ZD55 lacks the targeting ability for specific tumor type such as liver cancer. Thus, to improve the specific killing effect of oncolytic adenovirus on one type of cancer, one common strategy to design oncolytic adenoviruses is to use cancer or tissue-specific promoter to control the expression of viral essential gene for replication, which is the transcriptional targeted strategy [ 13 , 14 ]. It causes the viral gene selectively expression in tumor cells, then the virus could only replicate in and kill tumor cells [ 7 , 15 ].…”

Tumor Necrosis Factor α Regulates Endothelial Progenitor Cell Migration via CADM1 and NF-kB

“…Cell Adhesion Molecule 1 is a protein that has been found to be strongly expressed in neurons, [71][72][73][74][75] spermatogenic cells, [52,[76][77][78] immune cells, [79][80][81][82][83][84][85][86][87] and endothelial cells [88,89]. Functionally, CADM1 has been shown to participate in homophilic binding, and paradoxically, tumor suppression.…”

Oncolytic viruses against cancer stem cells: A promising approach for gastrointestinal cancer

“…Other than E1B detection, another common mutant of adenoviruses is the 24 bp deletion of the E1A retinoblastoma (Rb) binding site (∆24). Mutant adenoviruses show obvious tumor selectivity because viral replication is promoted in tumor cells with a defective Rb/p16 pathway and abolished in normal cells with intact Rb/p16[ 37 ]. Most cancer cells and CSCs harbor defects in the Rb and/or p53 pathway, which makes it possible to use OncoAd to eradicate the gastrointestinal cancer cells.…”