Control of cyclooxygenase-2 expression and tumorigenesis by endogenous 5-methoxytryptophan

Huei Hsuan Cheng; Cheng Chin Kuo; Jiann Long Yan; Hua Ling Chen; Wei Chung Lin; Kai Hsuan Wang; Kelvin K.C. Tsai; Hayrettin Guvén; Emilie Flaberg; Laszlo Szekelyd; George Klein; Kenneth K. Wu

doi:10.1073/pnas.1209919109

Control of cyclooxygenase-2 expression and tumorigenesis by endogenous 5-methoxytryptophan

Huei Hsuan Cheng, Cheng Chin Kuo, Jiann Long Yan, Hua Ling Chen, Wei Chung Lin, Kai Hsuan Wang, Kelvin K.C. Tsai, Hayrettin Guvén, Emilie Flaberg, Laszlo Szekelyd, George Klein, Kenneth K. Wu

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68 Scopus citations

Abstract

Cyclooxygenase-2 (COX-2) expression is induced by mitogenic and proinflammatory factors. Its overexpression plays a causal role in inflammation and tumorigenesis. COX-2 expression is tightly regulated, but the mechanisms are largely unclear. Here we show the control of COX-2 expression by an endogenous tryptophan metabolite, 5-methoxytryptophan (5-MTP). By using comparative metabolomic analysis and enzyme-immunoassay, our results reveal that normal fibroblasts produce and release 5-MTP into the extracellular milieu whereas A549 and other cancer cells were defective in 5-MTP production. 5-MTP was synthesized from L-tryptophan via tryptophan hydroxylase-1 and hydroxyindole O-methyltransferase. 5-MTP blocked cancer cell COX-2 overexpression and suppressed A549 migration and invasion. Furthermore, i.p. infusion of 5-MTP reduced tumor growth and cancer metastasis in a murine xenograft tumor model. We conclude that 5-MTP synthesis represents a mechanism for endogenous control of COX-2 overexpression and is a valuable lead for new anti-cancer and anti-inflammatory drug development.

Original language	English
Pages (from-to)	13231-13236
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	109
Issue number	33
DOIs	https://doi.org/10.1073/pnas.1209919109
State	Published - 14 Aug 2012
Externally published	Yes

Keywords

Inflammation control
Tryptophan metabolism
Tumor suppression

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10.1073/pnas.1209919109

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Cheng, H. H., Kuo, C. C., Yan, J. L., Chen, H. L., Lin, W. C., Wang, K. H., Tsai, K. K. C., Guvén, H., Flaberg, E., Szekelyd, L., Klein, G., & Wu, K. K. (2012). Control of cyclooxygenase-2 expression and tumorigenesis by endogenous 5-methoxytryptophan. Proceedings of the National Academy of Sciences of the United States of America, 109(33), 13231-13236. https://doi.org/10.1073/pnas.1209919109

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title = "Control of cyclooxygenase-2 expression and tumorigenesis by endogenous 5-methoxytryptophan",

abstract = "Cyclooxygenase-2 (COX-2) expression is induced by mitogenic and proinflammatory factors. Its overexpression plays a causal role in inflammation and tumorigenesis. COX-2 expression is tightly regulated, but the mechanisms are largely unclear. Here we show the control of COX-2 expression by an endogenous tryptophan metabolite, 5-methoxytryptophan (5-MTP). By using comparative metabolomic analysis and enzyme-immunoassay, our results reveal that normal fibroblasts produce and release 5-MTP into the extracellular milieu whereas A549 and other cancer cells were defective in 5-MTP production. 5-MTP was synthesized from L-tryptophan via tryptophan hydroxylase-1 and hydroxyindole O-methyltransferase. 5-MTP blocked cancer cell COX-2 overexpression and suppressed A549 migration and invasion. Furthermore, i.p. infusion of 5-MTP reduced tumor growth and cancer metastasis in a murine xenograft tumor model. We conclude that 5-MTP synthesis represents a mechanism for endogenous control of COX-2 overexpression and is a valuable lead for new anti-cancer and anti-inflammatory drug development.",

keywords = "Inflammation control, Tryptophan metabolism, Tumor suppression",

author = "Cheng, {Huei Hsuan} and Kuo, {Cheng Chin} and Yan, {Jiann Long} and Chen, {Hua Ling} and Lin, {Wei Chung} and Wang, {Kai Hsuan} and Tsai, {Kelvin K.C.} and Hayrettin Guv{\'e}n and Emilie Flaberg and Laszlo Szekelyd and George Klein and Wu, {Kenneth K.}",

year = "2012",

month = aug,

day = "14",

doi = "10.1073/pnas.1209919109",

language = "English",

volume = "109",

pages = "13231--13236",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

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publisher = "National Academy of Sciences",

number = "33",

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Cheng, HH, Kuo, CC, Yan, JL, Chen, HL, Lin, WC, Wang, KH, Tsai, KKC, Guvén, H, Flaberg, E, Szekelyd, L, Klein, G & Wu, KK 2012, 'Control of cyclooxygenase-2 expression and tumorigenesis by endogenous 5-methoxytryptophan', Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 33, pp. 13231-13236. https://doi.org/10.1073/pnas.1209919109

TY - JOUR

T1 - Control of cyclooxygenase-2 expression and tumorigenesis by endogenous 5-methoxytryptophan

AU - Cheng, Huei Hsuan

AU - Kuo, Cheng Chin

AU - Yan, Jiann Long

AU - Chen, Hua Ling

AU - Lin, Wei Chung

AU - Wang, Kai Hsuan

AU - Tsai, Kelvin K.C.

AU - Guvén, Hayrettin

AU - Flaberg, Emilie

AU - Szekelyd, Laszlo

AU - Klein, George

AU - Wu, Kenneth K.

PY - 2012/8/14

Y1 - 2012/8/14

N2 - Cyclooxygenase-2 (COX-2) expression is induced by mitogenic and proinflammatory factors. Its overexpression plays a causal role in inflammation and tumorigenesis. COX-2 expression is tightly regulated, but the mechanisms are largely unclear. Here we show the control of COX-2 expression by an endogenous tryptophan metabolite, 5-methoxytryptophan (5-MTP). By using comparative metabolomic analysis and enzyme-immunoassay, our results reveal that normal fibroblasts produce and release 5-MTP into the extracellular milieu whereas A549 and other cancer cells were defective in 5-MTP production. 5-MTP was synthesized from L-tryptophan via tryptophan hydroxylase-1 and hydroxyindole O-methyltransferase. 5-MTP blocked cancer cell COX-2 overexpression and suppressed A549 migration and invasion. Furthermore, i.p. infusion of 5-MTP reduced tumor growth and cancer metastasis in a murine xenograft tumor model. We conclude that 5-MTP synthesis represents a mechanism for endogenous control of COX-2 overexpression and is a valuable lead for new anti-cancer and anti-inflammatory drug development.

AB - Cyclooxygenase-2 (COX-2) expression is induced by mitogenic and proinflammatory factors. Its overexpression plays a causal role in inflammation and tumorigenesis. COX-2 expression is tightly regulated, but the mechanisms are largely unclear. Here we show the control of COX-2 expression by an endogenous tryptophan metabolite, 5-methoxytryptophan (5-MTP). By using comparative metabolomic analysis and enzyme-immunoassay, our results reveal that normal fibroblasts produce and release 5-MTP into the extracellular milieu whereas A549 and other cancer cells were defective in 5-MTP production. 5-MTP was synthesized from L-tryptophan via tryptophan hydroxylase-1 and hydroxyindole O-methyltransferase. 5-MTP blocked cancer cell COX-2 overexpression and suppressed A549 migration and invasion. Furthermore, i.p. infusion of 5-MTP reduced tumor growth and cancer metastasis in a murine xenograft tumor model. We conclude that 5-MTP synthesis represents a mechanism for endogenous control of COX-2 overexpression and is a valuable lead for new anti-cancer and anti-inflammatory drug development.

KW - Inflammation control

KW - Tryptophan metabolism

KW - Tumor suppression

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U2 - 10.1073/pnas.1209919109

DO - 10.1073/pnas.1209919109

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SN - 0027-8424

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SP - 13231

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JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 33

ER -

Control of cyclooxygenase-2 expression and tumorigenesis by endogenous 5-methoxytryptophan

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Keywords

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