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Discretionary Transduction of MMP-Sensitized Tousled in Head and Neck Cancer

Oral radiotoxicity is often a limiting factor in cancer treatment. Previously, we demonstrated that transfer of cell-permeable, TAT-fusion Tousled-like kinase 1B (TLK1B) protein in salivary glands effectively mitigates radiation-induced salivary dysfunction. However, similar to most radioprotectors,...

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Autores principales: Nair, Renjith Parameswaran, Timiri Shanmugam, Prakash Srinivasan, Sunavala-Dossabhoy, Gulshan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society of Gene & Cell Therapy 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6463741/
https://www.ncbi.nlm.nih.gov/pubmed/31011632
http://dx.doi.org/10.1016/j.omto.2019.02.003
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author Nair, Renjith Parameswaran
Timiri Shanmugam, Prakash Srinivasan
Sunavala-Dossabhoy, Gulshan
author_facet Nair, Renjith Parameswaran
Timiri Shanmugam, Prakash Srinivasan
Sunavala-Dossabhoy, Gulshan
author_sort Nair, Renjith Parameswaran
collection PubMed
description Oral radiotoxicity is often a limiting factor in cancer treatment. Previously, we demonstrated that transfer of cell-permeable, TAT-fusion Tousled-like kinase 1B (TLK1B) protein in salivary glands effectively mitigates radiation-induced salivary dysfunction. However, similar to most radioprotectors, TLK1B can carry the risk of limiting cancer treatment efficacy. The central goal of the study was, therefore, to reengineer TLK1B as a selective radioprotector of normal cells. Degradation of the extracellular matrix by proteases such as matrix metalloproteinases (MMPs) is a hallmark of aggressive tumors. Increased expression of membrane type 1-MMP (MT1-MMP; also called MMP14) is observed in a variety of cancers including head and neck squamous cell carcinoma (HNSCC). To limit TLK1B transduction to normal cells, we rendered the protein susceptible to MT1-MMP cleavage on the premise that high expression of MT1-MMP on the cell surface of HNSCC will suppress TLK1B internalization. Two optimal MT1-MMP-sensitive sequences (MS) were identified that when incorporated in TAT-TLK1B excluded its cellular entry in HNSCC, SCC40, but not immortalized salivary acinar cells, NS-SV-AC. Importantly, administration of MS-harboring TAT-TLK1B did not affect the sensitivity of tumors to radiation in a nude mouse xenograft tumor model. We conclude that a MMP-sensitive TLK1B can be an attractive therapeutic to allay salivary radiotoxicity without compromising cancer treatment efficacy.
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spelling pubmed-64637412019-04-22 Discretionary Transduction of MMP-Sensitized Tousled in Head and Neck Cancer Nair, Renjith Parameswaran Timiri Shanmugam, Prakash Srinivasan Sunavala-Dossabhoy, Gulshan Mol Ther Oncolytics Article Oral radiotoxicity is often a limiting factor in cancer treatment. Previously, we demonstrated that transfer of cell-permeable, TAT-fusion Tousled-like kinase 1B (TLK1B) protein in salivary glands effectively mitigates radiation-induced salivary dysfunction. However, similar to most radioprotectors, TLK1B can carry the risk of limiting cancer treatment efficacy. The central goal of the study was, therefore, to reengineer TLK1B as a selective radioprotector of normal cells. Degradation of the extracellular matrix by proteases such as matrix metalloproteinases (MMPs) is a hallmark of aggressive tumors. Increased expression of membrane type 1-MMP (MT1-MMP; also called MMP14) is observed in a variety of cancers including head and neck squamous cell carcinoma (HNSCC). To limit TLK1B transduction to normal cells, we rendered the protein susceptible to MT1-MMP cleavage on the premise that high expression of MT1-MMP on the cell surface of HNSCC will suppress TLK1B internalization. Two optimal MT1-MMP-sensitive sequences (MS) were identified that when incorporated in TAT-TLK1B excluded its cellular entry in HNSCC, SCC40, but not immortalized salivary acinar cells, NS-SV-AC. Importantly, administration of MS-harboring TAT-TLK1B did not affect the sensitivity of tumors to radiation in a nude mouse xenograft tumor model. We conclude that a MMP-sensitive TLK1B can be an attractive therapeutic to allay salivary radiotoxicity without compromising cancer treatment efficacy. American Society of Gene & Cell Therapy 2019-03-20 /pmc/articles/PMC6463741/ /pubmed/31011632 http://dx.doi.org/10.1016/j.omto.2019.02.003 Text en © 2019 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Nair, Renjith Parameswaran
Timiri Shanmugam, Prakash Srinivasan
Sunavala-Dossabhoy, Gulshan
Discretionary Transduction of MMP-Sensitized Tousled in Head and Neck Cancer
title Discretionary Transduction of MMP-Sensitized Tousled in Head and Neck Cancer
title_full Discretionary Transduction of MMP-Sensitized Tousled in Head and Neck Cancer
title_fullStr Discretionary Transduction of MMP-Sensitized Tousled in Head and Neck Cancer
title_full_unstemmed Discretionary Transduction of MMP-Sensitized Tousled in Head and Neck Cancer
title_short Discretionary Transduction of MMP-Sensitized Tousled in Head and Neck Cancer
title_sort discretionary transduction of mmp-sensitized tousled in head and neck cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6463741/
https://www.ncbi.nlm.nih.gov/pubmed/31011632
http://dx.doi.org/10.1016/j.omto.2019.02.003
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