Combined Inhibition of FOSL-1 and YAP Using siRNA-Lipoplexes Reduces the Growth of Pancreatic Tumor

Abstract

Pancreatic cancer evades most of the current therapies and there is an urgent need for new treatments that could efficiently eliminate this aggressive tumor, such as the blocking of routes driving cell proliferation. In this work, we propose the use of small interfering RNA (siRNA) to inhibit the combined expression of FOSL-1 and YAP, two signaling proteins related with tumor cell proliferation and survival. To improve the efficacy of cell transfection, DODAB:MO (1:2) liposomes were used as siRNA nanocarriers, forming a complex denominated siRNA-lipoplexes. Liposomes and lipoplexes (carrying two siRNA for each targeted protein, or the combination of four siRNAs) were physico-chemically and biologically characterized. They showed very good biocompatibility and stability. The efficient targeting of FOSL-1 and YAP expression at both mRNA and protein levels was first proved in vitro using mouse pancreatic tumoral cell lines (KRASG12V and p53 knockout), followed by in vivo studies using subcutaneous allografts on mice. The peri-tumoral injection of lipoplexes lead to a significant decrease in the tumor growth in both Athymic Nude-Foxn1nu and C57BL/6 mice, mainly in those receiving the combination of four siRNAs, targeting both YAP and FOSL-1. These results open a new perspective to overcome the fast tumor progression in pancreatic cancer.

Advances and Prospects in the Treatment of Pancreatic Cancer

“… 157 DODAB: MO (1:2) liposomes were employed as siRNA-lipid complexes prepared by siRNA nano-carriers, which could target FOSL-1 and YAP, leading to significant restrain of tumor growth. 158 Experiments revealed that the AuNRs complex could regulate the release of drugs under 665 nm light treatment, and exhibit synergistic antitumor effects when co-delivering siRNA and adriamycin based on gold nanorods. 159 A novel delivery system for gemcitabine and miR-21 inhibitors, based on dendritic-embedded gold nanoparticles and ultrasonic targeted microbubble destruction (UTMD) technology, showed great potential in the treatment of pancreatic cancer.…”

RAS‐targeted cancer therapy: Advances in drugging specific mutations

“…242 In other ways, sequential administration of cell-cycle kinases CDK4 and CDK6 inhibitors after taxane treatment reduced cell proliferation in PDAC mouse model with both KRAS G12V and Cdkn2a-null mutations. 243 Diego-González et al 244 found that lipoplexes of si-FOSL-1 and si-YAP reduce the tumor growth in mice carrying tumors induced by pancreatic tumoral cell lines (KRAS G12V and p53 knockout) through peri-tumoral injection.…”

“… 243 Diego‐González et al. 244 found that lipoplexes of si‐FOSL‐1 and si‐YAP reduce the tumor growth in mice carrying tumors induced by pancreatic tumoral cell lines (KRAS G12V and p53 knockout) through peri‐tumoral injection.…”