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Inhibition of tumor growth and metastasis by a combination of Escherichia coli-mediated cytolytic therapy and radiotherapy.

ABSTRACT: We have reported that Escherichia coli K-12 colonizes hypoxic and necrotic tumor regions after intravenous injection into tumor-bearing mice. In this study, we established a novel strategy for cancer therapy using engineered bacteria to enhance the therapeutic effects of radiation. E. coli strain K-12 was engineered to produce cytolysin A (ClyA), and its effects on tumor growth in primary and metastatic tumor models were evaluated. A single treatment with E. coli-expressing ClyA significantly decreased tumor growth rates initially (9 days after treatment); however, the tumors tended to grow thereafter. With only radiotherapy (RT; 21 Gy), the tumor growth rates were retarded, but not the tumor sizes. A combination of therapy with E. coli-expressing ClyA and radiation [a total of 5 x 10(7) colony-forming units (CFU) and 21 Gy] resulted in significant tumor shrinkage and even complete disappearance of tumors in mice with tumors derived from murine CT26 colon cancer. Furthermore, treatment with E. coli-expressing ClyA markedly suppressed metastatic tumor growth and prolonged the survival time in mice. The results described here indicate that therapy with engineered E. coli could significantly improve the results of RT, and could exert a striking inhibitory effect on the development of lung metastasis.

SUBMITTER: Jiang SN

PROVIDER: S-EPMC2839435 | biostudies-literature | 2010 Mar

REPOSITORIES: biostudies-literature

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Inhibition of tumor growth and metastasis by a combination of Escherichia coli-mediated cytolytic therapy and radiotherapy.

Jiang Sheng-Nan SN Phan Thuy X TX Nam Taek-Keun TK Nguyen Vu H VH Kim Hyung-Seok HS Bom Hee-Seung HS Choy Hyon E HE Hong Yeongjin Y Min Jung-Joon JJ

Molecular therapy : the journal of the American Society of Gene Therapy 20100105 3

We have reported that Escherichia coli K-12 colonizes hypoxic and necrotic tumor regions after intravenous injection into tumor-bearing mice. In this study, we established a novel strategy for cancer therapy using engineered bacteria to enhance the therapeutic effects of radiation. E. coli strain K-12 was engineered to produce cytolysin A (ClyA), and its effects on tumor growth in primary and metastatic tumor models were evaluated. A single treatment with E. coli-expressing ClyA significantly de ...[more]

PMID: 20051939

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Project description:UnlabelledThe absence of PtsN, the terminal phosphoacceptor of the phosphotransferase system comprising PtsP-PtsO-PtsN, in Escherichia coli confers a potassium-sensitive (K(s)) phenotype as the external K(+) concentration ([K(+)]e) is increased above 5 mM. A growth-inhibitory increase in intracellular K(+) content, resulting from hyperactivated Trk-mediated K(+) uptake, is thought to cause this K(s) We provide evidence that the K(s) of the ΔptsN mutant is associated with K(+) limitation. Accordingly, the moderate K(s) displayed by the ΔptsN mutant was exacerbated in the absence of the Trk and Kup K(+) uptake transporters and was associated with reduced cellular K(+) content. Conversely, overproduction of multiple K(+) uptake proteins suppressed the K(s) Expression of PtsN variants bearing the H73A, H73D, and H73E substitutions of the phosphorylation site histidine of PtsN complemented the K(s) Absence of the predicted inner membrane protein YcgO (also called CvrA) suppressed the K(s), which was correlated with elevated cellular K(+) content in the ΔptsN mutant, but the ΔptsN mutation did not alter YcgO levels. Heterologous overexpression of ycgO also led to K(s) that was associated with reduced cellular K(+) content, exacerbated by the absence of Trk and Kup and alleviated by overproduction of Kup. Our findings are compatible with a model that postulates that K(s) in the ΔptsN mutant occurs due to K(+) limitation resulting from activation of K(+) efflux mediated by YcgO, which may be additionally stimulated by [K(+)]e, implicating a role for PtsN (possibly its dephosphorylated form) as an inhibitor of YcgO activity.ImportanceThis study examines the physiological link between the phosphotransferase system comprising PtsP-PtsO-PtsN and K(+) ion metabolism in E. coli Studies on the physiological defect that renders an E. coli mutant lacking PtsN to be growth inhibited by external K(+) indicate that growth impairment results from cellular K(+) limitation that is mediated by YcgO, a predicted inner membrane protein. Additional observations suggest that dephospho-PtsN may inhibit and external K(+) may stimulate K(+) limitation mediated by YcgO. It is speculated that YcgO-mediated K(+) limitation may be an output of a response to certain stresses, which by modulating the phosphotransfer capacity of the PtsP-PtsO-PtsN phosphorelay leads to growth cessation and stress tolerance.

Dataset Information

Inhibition of tumor growth and metastasis by a combination of Escherichia coli-mediated cytolytic therapy and radiotherapy.

Publications

Inhibition of tumor growth and metastasis by a combination of Escherichia coli-mediated cytolytic therapy and radiotherapy.

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