Abstract |
We developed several adenoviral vectors designed to target MDA-7 expression to different subcellular compartments [endoplasmic reticulum (ER), mitochondria, nucleus, and cytosol] and evaluated their ability to enhance apoptosis. Adenoviral ER-targeted mda-7/ interleukin-24 vector (Ad-ER-mda7) selectively and effectively inhibited the growth and proliferation of lung (A549 and H1299) and esophageal (Seg1 and Bic1) cancer cells by enhancing cell killing. Both Ad-mda7 and Ad-ER-mda7 activated a novel pathway of ER stress-induced apoptosis characterized by unregulated expression of phosphorylated JNK, phosphorylated c-Jun, and phosphorylated RNA-dependent protein kinase. Caspase-4 activation mediated Ad-mda7- and Ad-ER-mda7-induced cell death. In addition, Ad-mda7- and Ad-ER-mda7-mediated growth inhibition correlated with activation of ER molecular markers RNA-dependent protein kinase and JNK both in vitro (in Ad-mda7- or Ad-ER-mda7-treated lung cancer cells) and in vivo. These findings suggest that vectors targeting the ER (Ad-ER-mda7) may be more effective in cancer gene therapy possibly through more effective induction or ER stress pathways.
|
Authors | Abujiang Pataer, Wenxian Hu, Lu Xiaolin, Sunil Chada, Jack A Roth, Kelly K Hunt, Stephen G Swisher |
Journal | Molecular cancer therapeutics
(Mol Cancer Ther)
Vol. 7
Issue 8
Pg. 2528-35
(Aug 2008)
ISSN: 1535-7163 [Print] United States |
PMID | 18723497
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
|
Chemical References |
- Interleukins
- interleukin-24
|
Topics |
- Adenoviridae
(genetics)
- Animals
- Cell Line, Tumor
- Endoplasmic Reticulum
(metabolism)
- Female
- Fluorescent Antibody Technique
- Genetic Vectors
- Interleukins
(genetics)
- Mice
- Mice, Nude
- Neoplasms
(pathology)
|