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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
p53 activated by AND gate genetic circuit under radiation and hypoxia for targeted cancer gene therapy
Miao Ding1, Rong Li2, Rong He3
1Department of Cardiology, Children Hospital, Chongqing Medical University, Chongqing, China.
Abstract:
Radio-activated gene therapy has been developed as a novel therapeutic strategy against cancer; however, expression of therapeutic gene in peritumoral tissues will result in unacceptable toxicity to normal cells. To restrict gene expression in targeted tumor mass, we used hypoxia and radiation tolerance features of tumor cells to develop a synthetic AND gate genetic circuit through connecting radiation sensitivity promoter cArG6 , heat shock response elements SNF1, HSF1 and HSE4 with retroviral vector plxsn. Their construction and dynamic activity process were identified through downstream enhanced green fluorescent protein and wtp53 expression in non-small cell lung cancer A549 cells and in a nude mice model. The result showed that AND gate genetic circuit could be activated by lower required radiation dose (6 Gy) and after activated, AND gate could induce significant apoptosis effects and growth inhibition of cancer cells in vitro and in vivo. The radiation- and hypoxia-activated AND gate genetic circuit, which could lead to more powerful target tumoricidal activity represented a promising strategy for both targeted and effective gene therapy of human lung adenocarcinoma and low dose activation character of the AND gate genetic circuit implied that this model could be further exploited to decrease side-effects of clinical radiation therapy.
Insights
A novel AND gate genetic circuit leverages tumor cell features to activate gene therapy specifically in cancer. This targeted approach enhances tumor cell apoptosis and growth inhibition, reducing toxicity to normal tissues.
Area of Science:
- Oncology
- Molecular Biology
- Biotechnology
Background:
- Radio-activated gene therapy offers cancer treatment potential but faces toxicity issues from peritumoral gene expression.
- Tumor cells' unique hypoxia and radiation tolerance features present an opportunity for targeted therapeutic strategies.
Purpose of the Study:
- To develop a synthetic AND gate genetic circuit for precise, tumor-specific gene expression in cancer therapy.
- To investigate the activation and efficacy of this circuit in non-small cell lung cancer models.
Main Methods:
- Constructed a synthetic AND gate genetic circuit using specific promoters (cArG6) and response elements (SNF1, HSF1, HSE4) on a retroviral vector (plxsn).
- Assessed circuit activity via downstream enhanced green fluorescent protein and wtp53 expression in A549 lung cancer cells and a nude mouse model.
- Evaluated the circuit's response to radiation and hypoxia, and its effects on cancer cell apoptosis and growth.
Main Results:
- The AND gate genetic circuit demonstrated activation at a low radiation dose (6 Gy).
- Activated circuit successfully induced significant apoptosis and growth inhibition in cancer cells both in vitro and in vivo.
- The circuit effectively restricted gene expression to the targeted tumor mass, minimizing off-target effects.
Conclusions:
- The developed radiation- and hypoxia-activated AND gate genetic circuit shows potent tumoricidal activity for targeted gene therapy in lung adenocarcinoma.
- The circuit's low-dose activation capability suggests potential for reducing side-effects in clinical radiation therapy.
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