Vitamin E metabolite 13′-carboxychromanols inhibit pro-inflammatory enzymes, induce apoptosis and autophagy in human cancer cells by modulating sphingolipids and suppress colon tumor development in mice

Yumi Jang; Na Young Park; Agnetha Linn Rostgaard-Hansen; Jianjie Huang; Qing Jiang

doi:10.1016/j.freeradbiomed.2016.03.018

Vitamin E metabolite 13′-carboxychromanols inhibit pro-inflammatory enzymes, induce apoptosis and autophagy in human cancer cells by modulating sphingolipids and suppress colon tumor development in mice

Yumi Jang, Na Young Park, Agnetha Linn Rostgaard-Hansen, Jianjie Huang, Qing Jiang^*

^*Corresponding author for this work

25 Citations (Scopus)

Abstract

Vitamin E forms are substantially metabolized to various carboxychromanols including 13′-carboxychromanols (13′-COOHs) that are found at high levels in feces. However, there is limited knowledge about functions of these metabolites. Here we studied δT-13′-COOH and δTE-13′-COOH, which are metabolites of δ-tocopherol and δ-tocotrienol, respectively. δTE-13′-COOH is also a natural constituent of a traditional medicine Garcinia Kola. Both 13′-COOHs are much stronger than tocopherols in inhibition of pro-inflammatory and cancer promoting cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX), and in induction of apoptosis and autophagy in colon cancer cells. The anticancer effects by 13′-COOHs appeared to be partially independent of inhibition of COX-2/5-LOX. Using liquid chromatography tandem mass spectrometry, we found that 13′-COOHs increased intracellular dihydrosphingosine and dihydroceramides after short-time incubation in HCT-116 cells, and enhanced ceramides while decreased sphingomyelins during prolonged treatment. Modulation of sphingolipids by 13′-COOHs was observed prior to or coinciding with biochemical manifestation of cell death. Pharmaceutically blocking the increase of these sphingolipids partially counteracted 13′-COOH-induced cell death. Further, 13′-COOH inhibited dihydroceramide desaturase without affecting the protein expression. In agreement with these mechanistic findings, δTE-13′-COOH significantly suppressed the growth and multiplicity of colon tumor in mice. Our study demonstrates that 13′-COOHs have anti-inflammatory and anticancer activities, may contribute to in vivo anticancer effect of vitamin E forms and are promising novel cancer prevention agents.

Original language	English
Journal	Free Radical Biology and Medicine
Volume	95
Pages (from-to)	190-199
Number of pages	10
ISSN	0891-5849
DOIs	https://doi.org/10.1016/j.freeradbiomed.2016.03.018
Publication status	Published - 2016
Externally published	Yes

Keywords

Apoptosis
Autophagy
Cancer
Sphingolipid
Vitamin E metabolites

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Jang, Y., Park, N. Y., Rostgaard-Hansen, A. L., Huang, J., & Jiang, Q. (2016). Vitamin E metabolite 13′-carboxychromanols inhibit pro-inflammatory enzymes, induce apoptosis and autophagy in human cancer cells by modulating sphingolipids and suppress colon tumor development in mice. Free Radical Biology and Medicine, 95, 190-199. https://doi.org/10.1016/j.freeradbiomed.2016.03.018

Vitamin E metabolite 13′-carboxychromanols inhibit pro-inflammatory enzymes, induce apoptosis and autophagy in human cancer cells by modulating sphingolipids and suppress colon tumor development in mice. / Jang, Yumi; Park, Na Young; Rostgaard-Hansen, Agnetha Linn et al.
In: Free Radical Biology and Medicine, Vol. 95, 2016, p. 190-199.

Research output: Contribution to journal › Journal article › Research › peer-review

Jang, Y, Park, NY, Rostgaard-Hansen, AL, Huang, J & Jiang, Q 2016, 'Vitamin E metabolite 13′-carboxychromanols inhibit pro-inflammatory enzymes, induce apoptosis and autophagy in human cancer cells by modulating sphingolipids and suppress colon tumor development in mice', Free Radical Biology and Medicine, vol. 95, pp. 190-199. https://doi.org/10.1016/j.freeradbiomed.2016.03.018

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title = "Vitamin E metabolite 13′-carboxychromanols inhibit pro-inflammatory enzymes, induce apoptosis and autophagy in human cancer cells by modulating sphingolipids and suppress colon tumor development in mice",

abstract = "Vitamin E forms are substantially metabolized to various carboxychromanols including 13′-carboxychromanols (13′-COOHs) that are found at high levels in feces. However, there is limited knowledge about functions of these metabolites. Here we studied δT-13′-COOH and δTE-13′-COOH, which are metabolites of δ-tocopherol and δ-tocotrienol, respectively. δTE-13′-COOH is also a natural constituent of a traditional medicine Garcinia Kola. Both 13′-COOHs are much stronger than tocopherols in inhibition of pro-inflammatory and cancer promoting cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX), and in induction of apoptosis and autophagy in colon cancer cells. The anticancer effects by 13′-COOHs appeared to be partially independent of inhibition of COX-2/5-LOX. Using liquid chromatography tandem mass spectrometry, we found that 13′-COOHs increased intracellular dihydrosphingosine and dihydroceramides after short-time incubation in HCT-116 cells, and enhanced ceramides while decreased sphingomyelins during prolonged treatment. Modulation of sphingolipids by 13′-COOHs was observed prior to or coinciding with biochemical manifestation of cell death. Pharmaceutically blocking the increase of these sphingolipids partially counteracted 13′-COOH-induced cell death. Further, 13′-COOH inhibited dihydroceramide desaturase without affecting the protein expression. In agreement with these mechanistic findings, δTE-13′-COOH significantly suppressed the growth and multiplicity of colon tumor in mice. Our study demonstrates that 13′-COOHs have anti-inflammatory and anticancer activities, may contribute to in vivo anticancer effect of vitamin E forms and are promising novel cancer prevention agents.",

keywords = "Apoptosis, Autophagy, Cancer, Sphingolipid, Vitamin E metabolites",

author = "Yumi Jang and Park, {Na Young} and Rostgaard-Hansen, {Agnetha Linn} and Jianjie Huang and Qing Jiang",

year = "2016",

doi = "10.1016/j.freeradbiomed.2016.03.018",

language = "English",

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pages = "190--199",

journal = "Free Radical Biology and Medicine",

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T1 - Vitamin E metabolite 13′-carboxychromanols inhibit pro-inflammatory enzymes, induce apoptosis and autophagy in human cancer cells by modulating sphingolipids and suppress colon tumor development in mice

AU - Jang, Yumi

AU - Park, Na Young

AU - Rostgaard-Hansen, Agnetha Linn

AU - Huang, Jianjie

AU - Jiang, Qing

PY - 2016

Y1 - 2016

N2 - Vitamin E forms are substantially metabolized to various carboxychromanols including 13′-carboxychromanols (13′-COOHs) that are found at high levels in feces. However, there is limited knowledge about functions of these metabolites. Here we studied δT-13′-COOH and δTE-13′-COOH, which are metabolites of δ-tocopherol and δ-tocotrienol, respectively. δTE-13′-COOH is also a natural constituent of a traditional medicine Garcinia Kola. Both 13′-COOHs are much stronger than tocopherols in inhibition of pro-inflammatory and cancer promoting cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX), and in induction of apoptosis and autophagy in colon cancer cells. The anticancer effects by 13′-COOHs appeared to be partially independent of inhibition of COX-2/5-LOX. Using liquid chromatography tandem mass spectrometry, we found that 13′-COOHs increased intracellular dihydrosphingosine and dihydroceramides after short-time incubation in HCT-116 cells, and enhanced ceramides while decreased sphingomyelins during prolonged treatment. Modulation of sphingolipids by 13′-COOHs was observed prior to or coinciding with biochemical manifestation of cell death. Pharmaceutically blocking the increase of these sphingolipids partially counteracted 13′-COOH-induced cell death. Further, 13′-COOH inhibited dihydroceramide desaturase without affecting the protein expression. In agreement with these mechanistic findings, δTE-13′-COOH significantly suppressed the growth and multiplicity of colon tumor in mice. Our study demonstrates that 13′-COOHs have anti-inflammatory and anticancer activities, may contribute to in vivo anticancer effect of vitamin E forms and are promising novel cancer prevention agents.

AB - Vitamin E forms are substantially metabolized to various carboxychromanols including 13′-carboxychromanols (13′-COOHs) that are found at high levels in feces. However, there is limited knowledge about functions of these metabolites. Here we studied δT-13′-COOH and δTE-13′-COOH, which are metabolites of δ-tocopherol and δ-tocotrienol, respectively. δTE-13′-COOH is also a natural constituent of a traditional medicine Garcinia Kola. Both 13′-COOHs are much stronger than tocopherols in inhibition of pro-inflammatory and cancer promoting cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX), and in induction of apoptosis and autophagy in colon cancer cells. The anticancer effects by 13′-COOHs appeared to be partially independent of inhibition of COX-2/5-LOX. Using liquid chromatography tandem mass spectrometry, we found that 13′-COOHs increased intracellular dihydrosphingosine and dihydroceramides after short-time incubation in HCT-116 cells, and enhanced ceramides while decreased sphingomyelins during prolonged treatment. Modulation of sphingolipids by 13′-COOHs was observed prior to or coinciding with biochemical manifestation of cell death. Pharmaceutically blocking the increase of these sphingolipids partially counteracted 13′-COOH-induced cell death. Further, 13′-COOH inhibited dihydroceramide desaturase without affecting the protein expression. In agreement with these mechanistic findings, δTE-13′-COOH significantly suppressed the growth and multiplicity of colon tumor in mice. Our study demonstrates that 13′-COOHs have anti-inflammatory and anticancer activities, may contribute to in vivo anticancer effect of vitamin E forms and are promising novel cancer prevention agents.

KW - Apoptosis

KW - Autophagy

KW - Cancer

KW - Sphingolipid

KW - Vitamin E metabolites

U2 - 10.1016/j.freeradbiomed.2016.03.018

DO - 10.1016/j.freeradbiomed.2016.03.018

M3 - Journal article

C2 - 27016075

AN - SCOPUS:84961927111

SN - 0891-5849

VL - 95

SP - 190

EP - 199

JO - Free Radical Biology and Medicine

JF - Free Radical Biology and Medicine

ER -