Cationic Liposome Mediated Delivery of FUS1 and hIL-12 Coexpression Plasmid Demonstrates Enhanced Activity against Human Lung Cancer

Abstract

FUS1 is one of the most important tumor suppressor genes in lung cancer, as well as an important immunomodulatory molecule. Interleukin (IL)-12 has attracted considerable interest as a potential anti-tumor cytokine. Cationic liposome has been shown to effectively deliver therapeutic genes to the lungs and control metastatic lung tumors when administered intravenously. Here we evaluated the enhanced efficacy of cationic liposome-mediated delivery of FUS1 and human IL (hIL)-12 eukaryotic coexpression plasmid (pVITRO2-FUS1-hIL-12) against the human lung cancer in HuPBL-NOD/SCID mice model by local and systemic administration, and explored the related molecular mechanism. Our study demonstrated that FUS1-hIL-12 coexpression could more sufficiently inhibit tumor growth and experimental lung metastasis, significantly prolong the survival of experimental lung metastasis mice. Moreover, FUS1-hIL-12 coexpression performed higher antitumor activity and lower toxicity in the inhibition of experimental lung metastatic tumor compared to cisplatin. We further identified that FUS1-hIL-12 coexpression could induce strong antitumor immune response by secreting much higher levels of human interferon-γ (hIFN-γ) and hIL-15, enhancing expression of MHC-I and Fas, increasing infiltration of activated human CD4+ and CD8+ T lymphocytes. FUS1-hIL-12 coexpression could also obviously induce tumor cell apoptosis and inhibit tumor cell proliferation partly by higher activation of STAT1 signal pathway and upregulation of p53. In addition, FUS1-hIL-12 coexpression also superiorly reduced the angiogenesis in tumors, which might be associated with downregulation of VEGF and VEGFR, and upregulation of human IP-10. Our results therefore suggest that cationic liposome-mediated FUS1-hIL-12 coexpression may be a new promising strategy for lung cancer treatment in clinical studies.

Mitochondria, calcium, and tumor suppressor Fus1: At the crossroad of cancer, inflammation, and autoimmunity

“…Stage I clinical trials of lipoparticles that deliver Fus1 transgene to compensate for Fus1 deficiency in tumors of patients with chemotherapy refractory stage IV lung cancer [ 27 ] showed no significant side effects, resulted in the uptake and expression of the gene by primary and metastatic tumors, and produced anti-tumor effects [ 28 ]. Introduction of cationic liposomes with Fus1/hIL-12 co-expression plasmid led to reduction of lung tumor growth in mice [ 29 ]. Based on these trials, a new strategy that combines Fus1 lipoparticles and other agents (LKB1 plasmid, AKT inhibitor MK2206) or established chemotherapy agents have been proposed [ 30 , 31 , 23 , 31 ].…”

TUSC2 Immunogene Therapy Synergizes with Anti–PD-1 through Enhanced Proliferation and Infiltration of Natural Killer Cells in Syngeneic Kras-Mutant Mouse Lung Cancer Models

“…TUSC2 regulates expression of critically important cytokines in the homeostasis and activation of the adaptive and innate immune system (e.g., IL2 and IL15) (4, 11). Natural Killer (NK) cell–mediated innate immune activation is an important component of TUSC2 gene therapy.…”

The TUSC2 Tumour Suppressor Inhibits the Malignant Phenotype of Human Thyroid Cancer Cells via SMAC/DIABLO Protein

“…TUSC2 has pro-apoptotic activity in human lung cancer cells through the regulation of the protein kinases EGFR, PDGFR, AKT, c-ABL, and c-KIT [3,10], through the activation of the STAT1 signal pathway and through regulation of the P53 protein [26].…”