Synergistic effects of eukaryotic coexpression plasmid carrying LKB1 and FUS1 genes on lung cancer in vitro and in vivo.

Abstract

PURPOSE:

LKB1 and FUS1 are two kinds of new tumor suppressor genes as well as early-stage genes in lung cancer. Recent studies showed that LKB1 and FUS1 play important roles in lung carcinogenesis process. We hypothesized that combined gene therapy with LKB1 and FUS1 could inhibit lung cancer growth and development synergistically.

METHODS:

In this study, two kinds of tumor suppressor genes, LKB1 and FUS1, were constructed in an eukaryotic coexpression plasmid pVITRO(2), and then, we evaluated the synergistic effects of the two genes on anticancer activity and explored the relevant molecular mechanisms.

RESULTS:

We defined coexpression of LKB1 and FUS1 could synergistically inhibited lung cancer cells growth,invasion and migration and induced the cell apoptosis and arrested cell cycle in vitro. Intratumoral administration of liposomes: pVITRO(2)–LKB1–FUS1 complex (LPs–pVITRO(2)–LKB1–FUS1) into subcutaneous lung tumor xenograft resulted in more significant inhibition of tumor growth. Furthermore, intravenous injection of LPs–pVITRO(2)–LKB1–FUS1 into mice bearing experimental A549 lung metastasis demonstrated synergistic decrease in the number of metastatic tumor nodules. Finally, combined treatment with LKB1 and FUS1 prolonged overall survival in lung tumor-bearing mice. Further study showed tha tthe synergistic anti-lung cancer effects of coexpression ofLKB1 and FUS1 might be related to upregulation of p-p53, p-AMPK and downregulation of p-mTOR, p-FAK, MMPs, NEDD9, VEGF/R and PDGF/R.

CONCLUSIONS:

Our results suggest that combined therapy with eukaryotic coexpression plasmid carrying LKB1 and FUS1 genes may be a novel and efficient treatment strategy for human lung cancer.

• Authors: Lingdong Li, Chuanjiang Yu, Jiang Ren, Sujuan Ye, Wenjing Ou, Yu Wang, Weihan Yang, Guoxing Zhong, Xiang Chen, Huashan Shi, Xiaolan Su, Lijuan Chen, Wen Zhu
• Journal: Journal of cancer research and clinical oncology (J Cancer Res Clin Oncol) Vol. 140 Issue 6 Pg. 895-907 (Jun 2014) ISSN: 1432-1335 [Electronic] Germany
• PMID: 24659339 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• TUSC2 protein, human
• Tumor Suppressor Proteins
• Protein Serine-Threonine Kinases
• STK11 protein, human
• AMP-Activated Protein Kinase Kinases

Topics

• AMP-Activated Protein Kinase Kinases
• Animals
• Apoptosis
• Blotting, Western
• Carcinoma, Non-Small-Cell Lung (genetics, prevention & control, secondary)
• Cell Adhesion
• Cell Cycle
• Cell Movement
• Cell Proliferation
• Drug Synergism
• Female
• Genetic Therapy
• Humans
• In Vitro Techniques
• Lung Neoplasms (genetics, pathology, prevention & control)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Protein Serine-Threonine Kinases (genetics, metabolism)
• Tumor Cells, Cultured
• Tumor Suppressor Proteins (genetics, metabolism)
• Xenograft Model Antitumor Assays