Antisense-mediated hTERT inhibition specifically reduces the growth of human bladder cancer cells
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An Orthotopic Bladder Tumor Model and the Evaluation of Intravesical saRNA Treatment
Published on: July 28, 2012
Kai Kraemer1, Susanne Fuessel, Uta Schmidt
1Department of Urology, Technical University Dresden, D-01307, Dresden, Germany.
Purpose:
The expression of human telomerase reverse transcriptase (hTERT) is associated with cellular aging and tumorigenesis. It was found in nearly all cancer types but not in most normal, somatic cells. The aim of this study was to investigate whether hTERT inhibition by antisense oligodeoxynucleotides (AS-ODN) can act as an efficient strategy to specifically impair the growth of bladder cancer (BCa) cells in vitro.
Experimental Design:
Twenty-three AS-ODNs were designed complementary to five putative single-stranded target sites using a computer-aided secondary structure prediction of hTERT mRNA. The BCa cell lines were transfected once or several times with AS-ODNs, and the influences on cell growth, hTERT mRNA, and hTERT protein levels, as well as on telomerase activity, were examined.
Results:
An immediate and continuous reduction of cell viability (up to a complete cell loss) was achieved by treatment with 5 of 23 tested AS-ODNs in EJ28 cells. Additionally, significant inhibition of proliferation (doubling time, clonogenic survival), as well as an induction of G(1) arrest were observed. The specificity of the growth-inhibitory action of the five efficient AS-ODNs was confirmed by diminished hTERT transcript amount (< or =88%) and reduced hTERT protein content in EJ28 cells. As a consequence, the telomerase activity was inhibited by anti-hTERT treatment < or =60%. Inhibition of viability was shown for an additional three tested BCa cell lines but not for primary fibroblasts after treatment with the five most effective AS-ODNs supporting an antitumor action of these constructs.
Conclusion:
Specific hTERT inhibition causes remarkable short- and long-term effects on the growth of BCa cells and represents a promising new treatment option of solid tumors. We propose that this alternative treatment could be applied in terms of an instillation therapy.
Insights
Antisense oligodeoxynucleotides (AS-ODN) targeting human telomerase reverse transcriptase (hTERT) effectively inhibited bladder cancer cell growth in vitro. This targeted hTERT inhibition offers a promising strategy for solid tumor treatment.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Human telomerase reverse transcriptase (hTERT) expression is linked to cellular aging and cancer development.
- hTERT is prevalent in most cancer types but absent in normal somatic cells, making it a potential therapeutic target.
- Bladder cancer (BCa) is a significant health concern where targeting hTERT could offer novel treatment avenues.
Purpose of the Study:
- To evaluate the efficacy of inhibiting human telomerase reverse transcriptase (hTERT) using antisense oligodeoxynucleotides (AS-ODN).
- To determine if AS-ODN-mediated hTERT inhibition can specifically impede the in vitro growth of bladder cancer (BCa) cells.
- To explore a potential new therapeutic strategy for solid tumors, including bladder cancer.
Main Methods:
- Designed 23 AS-ODNs targeting hTERT mRNA based on secondary structure predictions.
- Transfected bladder cancer cell lines with AS-ODNs to assess impacts on cell viability, proliferation, and hTERT expression.
- Quantified hTERT mRNA and protein levels, telomerase activity, and cell cycle progression (G1 arrest).
Main Results:
- Five out of 23 AS-ODNs significantly reduced viability, induced G1 arrest, and inhibited proliferation in EJ28 bladder cancer cells.
- Effective AS-ODNs decreased hTERT mRNA by up to 88% and protein by a substantial amount, leading to up to 60% telomerase activity inhibition.
- The five most effective AS-ODNs inhibited viability in three additional BCa cell lines but not in primary fibroblasts, indicating tumor-specific action.
Conclusions:
- Specific inhibition of hTERT by AS-ODNs demonstrates significant short- and long-term anti-proliferative effects on bladder cancer cells.
- Targeting hTERT represents a promising therapeutic approach for solid tumors.
- Instillation therapy is proposed as a potential application method for this treatment strategy.
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