Metabolic engineering of probiotic Escherichia coli for cytolytic therapy of tumors

Abstract Bacterial cancer therapy was developed using probiotic Escherichia coli Nissle 1917 (EcN) for medical intervention of colorectal cancer. EcN was armed with HlyE, a small cytotoxic protein, under the control of the araBAD promoter (PBAD). The intrinsic limitation of PBAD for the gene express...

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Autores principales:	Chung-Jen Chiang, Po-Han Huang
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/ee22a175ea4c4ede806630b19979fd3b
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spelling	oai:doaj.org-article:ee22a175ea4c4ede806630b19979fd3b2021-12-02T13:30:42ZMetabolic engineering of probiotic Escherichia coli for cytolytic therapy of tumors10.1038/s41598-021-85372-62045-2322https://doaj.org/article/ee22a175ea4c4ede806630b19979fd3b2021-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-85372-6https://doaj.org/toc/2045-2322Abstract Bacterial cancer therapy was developed using probiotic Escherichia coli Nissle 1917 (EcN) for medical intervention of colorectal cancer. EcN was armed with HlyE, a small cytotoxic protein, under the control of the araBAD promoter (PBAD). The intrinsic limitation of PBAD for the gene expression is known to be negated by glucose and afflicted with all-or-nothing induction in host bacteria. This issue was addressed by metabolic engineering of EcN to uncouple the glucose-mediated control circuit and the L-arabinose transport-induction loop and to block L-arabinose catabolism. As a result, the reprogrammed strain (designated EcNe) enabled efficient expression of HlyE in a temporal control manner. The HlyE production was insensitive to glucose and reached a saturated level in response to L-arabinose at 30–50 μM. Moreover, the administrated EcNe exhibited tumor-specific colonization with the tumor-to-organ ratio of 106:1. Equipped with HlyE, EcNe significantly caused tumor regression in mice xenografted with human colorectal cancer cells. Overall, this study proposes a new strategy for the bacteria-mediated delivery of therapeutic proteins to tumors.Chung-Jen ChiangPo-Han HuangNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-18 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Chung-Jen Chiang Po-Han Huang Metabolic engineering of probiotic Escherichia coli for cytolytic therapy of tumors
description	Abstract Bacterial cancer therapy was developed using probiotic Escherichia coli Nissle 1917 (EcN) for medical intervention of colorectal cancer. EcN was armed with HlyE, a small cytotoxic protein, under the control of the araBAD promoter (PBAD). The intrinsic limitation of PBAD for the gene expression is known to be negated by glucose and afflicted with all-or-nothing induction in host bacteria. This issue was addressed by metabolic engineering of EcN to uncouple the glucose-mediated control circuit and the L-arabinose transport-induction loop and to block L-arabinose catabolism. As a result, the reprogrammed strain (designated EcNe) enabled efficient expression of HlyE in a temporal control manner. The HlyE production was insensitive to glucose and reached a saturated level in response to L-arabinose at 30–50 μM. Moreover, the administrated EcNe exhibited tumor-specific colonization with the tumor-to-organ ratio of 106:1. Equipped with HlyE, EcNe significantly caused tumor regression in mice xenografted with human colorectal cancer cells. Overall, this study proposes a new strategy for the bacteria-mediated delivery of therapeutic proteins to tumors.
format	article
author	Chung-Jen Chiang Po-Han Huang
author_facet	Chung-Jen Chiang Po-Han Huang
author_sort	Chung-Jen Chiang
title	Metabolic engineering of probiotic Escherichia coli for cytolytic therapy of tumors
title_short	Metabolic engineering of probiotic Escherichia coli for cytolytic therapy of tumors
title_full	Metabolic engineering of probiotic Escherichia coli for cytolytic therapy of tumors
title_fullStr	Metabolic engineering of probiotic Escherichia coli for cytolytic therapy of tumors
title_full_unstemmed	Metabolic engineering of probiotic Escherichia coli for cytolytic therapy of tumors
title_sort	metabolic engineering of probiotic escherichia coli for cytolytic therapy of tumors
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/ee22a175ea4c4ede806630b19979fd3b
work_keys_str_mv	AT chungjenchiang metabolicengineeringofprobioticescherichiacoliforcytolytictherapyoftumors AT pohanhuang metabolicengineeringofprobioticescherichiacoliforcytolytictherapyoftumors
_version_	1718392948614234112

Metabolic engineering of probiotic Escherichia coli for cytolytic therapy of tumors

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