Reversing Translational Suppression and Induction of Toxicity in Pancreatic Cancer Cells Using a Chemoprevention Gene Therapy Approach

Abstract

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.

Role of MDA-7/IL-24 a Multifunction Protein in Human Diseases

“…So far, researchers have confirmed that MDA-7/IL-24 is not only involved in normal immune function and wound healing, but it also has several additional beneficial effects in a variety of human diseases. As examples, MDA-7/IL-24 functions as an anticancer gene in multiple diverse cancers including melanoma (Lebedeva et al, 2002; Sarkar et al, 2008), prostate cancer (Greco et al, 2010; Lebedeva, Sarkar, et al, 2003; Lebedeva, Su, Sarkar, & Fisher, 2003), breast cancer (Bhutia et al, 2013; Menezes et al, 2015; Pradhan et al, 2017; Sarkar et al, 2005), osteosarcoma (Zhuo et al, 2017), neuroblastoma (Bhoopathi et al, 2016), pancreatic cancer (Sarkar, Quinn, Shen, Dent, et al, 2015), renal carcinoma (Park et al, 2009), leukemia (Rahmani et al, 2010), lung cancer (Lv, Su, Liang, Hu, & Yuan, 2016; Shapiro et al, 2016), esophageal squamous cell carcinoma (Ma, Jin, et al, 2016), and hepatocellular carcinoma (Wang, Ye, Zhong, Xiang, & Yang, 2007). MDA-7/IL-24 provides protection against autoimmune diseases and bacterial infections (Leng, Pan, Tao, & Ye, 2011; Ma et al, 2009).…”

Chemoprevention and Treatment of Pancreatic Cancer: Update and Review of the Literature

“…Perillyl alcohol induces Bak-dependent apoptosis, but it does not significantly increase the survival rate [66,130]. Perillyl alcohol in combination with conditional replication competent adenoviruses, which selectively replicate in cancer cells with simultaneous expression of melanoma differentiation associated gene-7/interleukin-24, features chemopreventive effects via the induction of apoptosis by inhibiting b-cell lymphoma-extra large (Bcl-xL) and Bcl-2 [131,132]. 0.001]; and PanIN-3, 7-34% [p < 0.0141]) as well [133].…”

Clinical Significance of the Interleukin 24 mRNA Level in Head and Neck Squamous Cell Carcinoma and Its Subgroups: An In Silico Investigation

“…IL24 has also been found in many diseases involving inflammation, such as cardiovascular disease, rheumatoid arthritis, tuberculosis , and viral infections, and may play a role in psoriasis [ 15 , 36 ]. In addition, many studies have shown that IL24 mRNA can be used as a potential tumor treatment [ 37 , 38 ]. All these characteristics suggest that the IL24 mRNA may provide a potential idea for the treatment of HNSCC and its subgroups, which is significant for further research with a larger sample size.…”