Abstract
Activatable cell-penetrating peptides (aCPPs) allow non-viral, low cytotoxic and selective delivery of compounds into target cells for cancer therapy. In tumour cells, up-regulation of human telomerase reverse transcriptase (hTERT) frequently occurs and is being considered as a target in cancer diagnosis and treatment. siRNA sequence that target hTERT mRNA can silence the gene and reduce hTERT protein expression to reduce cell proliferation and inhibit cell growth. In our study, we tested a matrix metalloproteinase-2 (MPP2) aCPP in delivering hTERT siRNA into hepatocellular carcinoma cells (SMMC-7721) to silence the hTERT gene. Cultured SMMC-7721 cells were transfected with a complex of aCPPs and hTERT-specific siRNA-encoding or control plasmids. Compared with cells treated with the complex of control plasmid–CPPs, cells treated with the hTERT-specific siRNA-encoding plasmid–CPP complex had a prolonged G1-phase, but a shorter G2/S-phase, indicating a G1-arrest. Treatment with the hTERT-specific siRNA resulted in a significant decrease (by 26%; P<0.05) in hTERT mRNA levels. The aCPPs tested in this study provides a non-viral delivery of siRNA into cancer cells to silence target genes in cancer therapy.
Highlights
Cell-penetrating peptides (CPPs) are short peptides, typically 5– 30 amino acids in length that can carry a variety of substances into the eukaryotic cytoplasm and even into the nucleus, having little cytotoxicity [1]
The concept of targeted activation of CPPs was pioneered by Jiang et al [5], in which they constructed Activatable cell-penetrating peptides (aCPPs) that can only be activated when the linkers are cleaved by matrix metalloproteinases (MMPs), releasing the CPPs from inhibitory polyanions
Our study demonstrated the effectiveness of MMP2 aCPPs as a non-viral method of introducing human telomerase reverse transcriptase (hTERT) siRNA into hepatoma cells to suppress the expression of hTERT
Summary
Cell-penetrating peptides (CPPs) are short peptides, typically 5– 30 amino acids in length that can carry a variety of substances into the eukaryotic cytoplasm and even into the nucleus, having little cytotoxicity [1]. CPPs have been explored widely for their potential in various therapeutics [2]. They have been applied and are being developed for application in in vivo and in vitro experiments involving malignancies such as breast cancer, ovarian cancer, prostate cancer and colon cancer [3,4,5,6]. CPPs are capable of delivering a variety of molecular cargo across the cell membrane for cancer therapy [7]. The activated CPPs and cargo are able to attach and cross cell membranes. This strategy provides a solution to selectively target tumours in cancer therapy, as MMPs are the most well-known proteases overexpressed by tumours. A majority of malignant tumours express MMP2; the expression of which is associated with the degree of malignancy, tumour angiogenesis, invasiveness and metastasis [9,10,11,12,13,14]
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