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Tumour regression in a ligand inducible manner mediated by a chimeric tumour suppressor derived from p53
S Sengupta1, R Ralhan, B Wasylyk
1Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, Illkirch, France.
Abstract:
The p53 tumour suppressor induces cell cycle arrest and apoptosis in response to cellular stresses. p53 is inactivated by various cellular and viral factors. We set out to generate regulatable p53 derivatives that are highly inducible by synthetic ligands, escape inactivation and efficiently induce apoptosis. We have generated Ligand Inducible Chimeric Tumour Suppressors (LI-CTS), that are inactive unless provided with artificial ligands. They are resistant to inactivation, due to the replacement of domains that mediate p53 inhibition by heterologous sequences. LI-CTS are activated by micromolar concentrations of ligand in a variety of cell lines. Following ligand addition, they translocate to the nucleus, activate p53 inducible genes and induce apoptosis. We have established human head and neck squamous cell carcinoma lines that stably express LI-CTS, which are inducible. These lines form tumours in nude mice in the absence of ligand. Addition of ligand inhibits tumour formation, and moreover, regresses established tumours by apoptosis. Although regulatable p53 expression has been achieved previously, our study provides the first demonstration of regulatable in vivo regression of tumours in a p53 based approach. Regulated inhibition and regression of tumours with a ligand inducible chimeric tumour suppressor could provide a novel approach to p53 based gene therapy.
Insights
Researchers developed novel Ligand Inducible Chimeric Tumour Suppressors (LI-CTS) that are resistant to inactivation. These engineered p53 derivatives effectively induce apoptosis and inhibit tumor growth in vivo upon ligand administration, offering a new gene therapy approach.
Area of Science:
- Oncology
- Molecular Biology
- Gene Therapy
Background:
- The p53 tumor suppressor is crucial for inducing cell cycle arrest and apoptosis in response to cellular stress.
- p53 function is frequently compromised by cellular and viral factors, hindering its tumor-suppressive activity.
- Developing strategies to restore or enhance p53 activity is vital for cancer treatment.
Purpose of the Study:
- To engineer novel, regulatable p53 derivatives that are highly inducible by synthetic ligands.
- To create p53 variants resistant to inactivation by cellular and viral factors.
- To demonstrate the efficacy of these engineered p53 derivatives in inducing apoptosis and controlling tumor growth in vivo.
Main Methods:
- Generation of Ligand Inducible Chimeric Tumour Suppressors (LI-CTS) by replacing inhibitory domains with heterologous sequences.
- Assessment of LI-CTS activity in various cell lines upon addition of synthetic ligands.
- Establishment of human head and neck squamous cell carcinoma lines stably expressing LI-CTS.
- In vivo studies using tumor xenografts in nude mice to evaluate LI-CTS-mediated tumor inhibition and regression.
Main Results:
- LI-CTS were successfully generated and demonstrated ligand-dependent activation at micromolar concentrations.
- Activated LI-CTS translocated to the nucleus, induced p53 target genes, and triggered apoptosis in cancer cell lines.
- Stable LI-CTS expressing cell lines inhibited tumor formation and regressed established tumors in vivo following ligand administration.
- This study presents the first demonstration of ligand-inducible in vivo tumor regression using a p53-based approach.
Conclusions:
- Ligand Inducible Chimeric Tumour Suppressors (LI-CTS) offer a robust, regulatable system to restore p53 tumor-suppressive functions.
- LI-CTS are resistant to inactivation and can effectively induce apoptosis and mediate tumor regression in a controlled manner.
- Regulated tumor inhibition and regression via LI-CTS represent a promising novel strategy for p53-based gene therapy.