hTERT/re-caspase-3 system induce apoptosis in hTERT-positive

Abstract

Apoptosis induction is a promising approach for the treatment of human cancer. To achieve this purpose, the design of an expression system capable to induce apoptosis specifically in cancer cells is essential. Telomerase is an attractive target for delivery of apoptotic genes as an overwhelming majority of cancers have telomerase activity whereas most normal cells have low or an absence of telomerase activity. Activation of telomerase is tightly regulated at the transcriptional level of human telomerase reverse transcriptase (hTERT). In the present study, we developed a telomerase-specific delivery system of apoptosis-inducible gene re-Caspase-3, through utilizing the promoter of the hTERT gene, and then investigated its antitumor effect on cancer cells and tissues. The reason we used the re-Caspase-3 gene is that it is capable of autocatalytic processing and inducing apoptosis independent of the initiator Caspases. Here, we demonstrated that the hTERT/re-Caspase-3 system induced apoptosis in hTERT-positive cancer cells: CNE1 (nasopharyngeal carcinoma), HRT-18 (colonic carcinoma), MGC (stomath carcinoma), but not in hTERT-low Hacat (human normal keratinize epithelium) cells. In addition, the growth of s.c. tumors in nude mice was suppressed significantly by the treatment with the hTERT/re-Caspase-3 system. Results suggested that the telomerase-specific transfer of the re-Caspase-3 gene may be an effective and promising targeting approach for the treatment of cancer.

nm23‐H1 gene driven by hTERT promoter induces inhibition of invasive phenotype and metastasis of lung cancer xenograft in mice

“…Several studies described constructs containing propapoptotic transgenes controlled by the tumor‐selective promoters of hTERT. For instance, caspase 3, 37 caspase 6, 38 FADD, 39 diphtheria toxin A chain (DT‐A), 40 death receptor 4 (DR‐4), 41 TRAIL 42 or Bax 43 were used under hTERT promoter control. Furthermore, the suicide gene has been introduced to the hTERT therapeutic system after encouraging results in transfection experiments with human herpes simplex virus thymidine kinase (HSV‐TK), 44 cytosine deaminase (CD) 45 and nitroreductase (NTR); different groups incorporated HSV‐TK 44,46–48 or NTR 49 .…”

Targeting apoptosis to cancer via hTERT promoter

“…3 In this issue of Cancer Biology & Therapy, Yang et al report using the hTERT promoter-driving constitutive caspase 3 for cancer gene therapy. 4 The authors demonstrate that hTERT/re-Caspase-3 can effectively induce apoptosis in vitro and in vivo in cancer cells from nasopharyngeal carcinoma, colonic carcinoma, and stomach carcinoma, further demonstrating the general application of such a strategy in cancer therapy.…”

“…3,4 In both studies, the researchers used the hTERT promoter for expression of the constitutive caspase genes. Telomerase, a reverse transcriptase responsible for the replication of telomeres, is overexpressed in more than 85% of cancers, regardless of their origins of tissues.…”

“…This is further supported by the manuscript by Yang et al, which demonstrates that hTERT/re-Caspase-3 is effective against cancer cells derived from the nasopharynx, colon, and stomach. 4 However, it is notable that strategies to enhance hTERT promoter activity will be desirable for cancer gene therapy. As shown in the paper of Yang et al, the levels of transgene expression from the hTERT promoter is still relatively lower than that from the cytomegalovirus promoter.…”

Regulation of Mcl-1 by constitutive activation of NF-kappaB contributes to cell viability in human esophageal squamous cell carcinoma cells

“…Human esophageal carcinoma cell lines KYSE150 and KYSE510 were kindly provided by Dr. Qian Tao from The Chinese University of Hong Kong, HongKong, China. Immortalized human keratinocyte cell line HaCaT derived from human adult trunk skin was previous described [27,28]. TE-1, Eca109, KYSE150 and KYSE510 cells were cultured in RPMI 1640 medium (Invitrogen, Carlsbad, CA) supplemented with 10% fetal bovine serum, 100 units/ml penicillin and 100 mg/ml streptomycin.…”