RT Journal Article
SR Electronic
T1 Reversing Translational Suppression and Induction of Toxicity in Pancreatic Cancer Cells Using a Chemoprevention Gene Therapy Approach
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 286
OP 295
DO 10.1124/mol.114.094375
VO 87
IS 2
A1 Siddik Sarkar
A1 Bridget A. Quinn
A1 Xuening Shen
A1 Paul Dent
A1 Swadesh K. Das
A1 Luni Emdad
A1 Devanand Sarkar
A1 Paul B. Fisher
YR 2015
UL http://molpharm.aspetjournals.org/content/87/2/286.abstract
AB Pancreatic cancer is an aggressive disease with limited therapeutic options. Melanoma differentiation–associated gene-7/interleukin-24 (mda-7/IL-24), a potent antitumor cytokine, shows cancer-specific toxicity in a vast array of human cancers, inducing endoplasmic reticulum stress and apoptosis, toxic autophagy, an antitumor immune response, an antiangiogenic effect, and a significant “bystander” anticancer effect that leads to enhanced production of this cytokine through autocrine and paracrine loops. Unfortunately, mda-7/IL-24 application in pancreatic cancer has been restricted because of a “translational block” occurring after Ad.5-mda-7 gene delivery. Our previous research focused on developing approaches to overcome this block and increase the translation of the MDA-7/IL-24 protein, thereby promoting its subsequent toxic effects in pancreatic cancer cells. We demonstrated that inducing reactive oxygen species (ROS) after adenoviral infection of mda-7/IL-24 leads to greater translation into MDA-7/IL-24 protein and results in toxicity in pancreatic cancer cells. In this study we demonstrate that a novel chimeric serotype adenovirus, Ad.5/3-mda-7, displays greater efficacy in delivering mda-7/IL-24 compared with Ad.5-mda-7, although overall translation of the protein still remains low. We additionally show that d-limonene, a dietary monoterpene known to induce ROS, is capable of overcoming the translational block when used in combination with adenoviral gene delivery. This novel combination results in increased polysome association of mda-7/IL-24 mRNA, activation of the preinitiation complex of the translational machinery in pancreatic cancer cells, and culminates in mda-7/IL-24–mediated toxicity.