γ-Tocotrienol induces growth arrest through a novel pathway with TGFβ2 in prostate cancer

Sharon E. Campbell; Brittney Rudder; Regenia B. Phillips; Sarah G. Whaley; Julie B. Stimmel; Lisa M. Leesnitzer; Janet Lightner; Sophie Dessus-Babus; Michelle Duffourc; William L. Stone; David G. Menter; Robert A. Newman; Peiying Yang; Bharat B. Aggarwal; Koyamangalath Krishnan

doi:10.1016/j.freeradbiomed.2011.02.007

γ-Tocotrienol induces growth arrest through a novel pathway with TGFβ2 in prostate cancer

Sharon E. Campbell, Brittney Rudder, Regenia B. Phillips, Sarah G. Whaley, Julie B. Stimmel, Lisa M. Leesnitzer, Janet Lightner, Sophie Dessus-Babus, Michelle Duffourc, William L. Stone, David G. Menter, Robert A. Newman, Peiying Yang, Bharat B. Aggarwal, Koyamangalath Krishnan

Research output: Contribution to journal › Article › peer-review

41 Scopus citations

Abstract

Regions along the Mediterranean and in southern Asia have lower prostate cancer incidence compared to the rest of the world. It has been hypothesized that one of the potential contributing factors for this low incidence includes a higher intake of tocotrienols. Here we examine the potential of γ-tocotrienol (GT3) to reduce prostate cancer proliferation and focus on elucidating pathways by which GT3 could exert a growth-inhibitory effect on prostate cancer cells. We find that the γ and δ isoforms of tocotrienol are more effective at inhibiting the growth of prostate cancer cell lines (PC-3 and LNCaP) compared with the γ and δ forms of tocopherol. Knockout of PPAR-γ and GT3 treatment show inhibition of prostate cancer cell growth, through a partially PPAR-γ-dependent mechanism. GT3 treatment increases the levels of the 15-lipoxygenase-2 enzyme, which is responsible for the conversion of arachidonic acid to the PPAR-γ-activating ligand 15-S-hydroxyeicosatrienoic acid. In addition, the latent precursor and the mature forms of TGFβ2 are down-regulated after treatment with GT3, with concomitant disruptions in TGFβ receptor I, SMAD-2, p38, and NF-κB signaling.

Original language	English (US)
Pages (from-to)	1344-1354
Number of pages	11
Journal	Free Radical Biology and Medicine
Volume	50
Issue number	10
DOIs	https://doi.org/10.1016/j.freeradbiomed.2011.02.007
State	Published - May 15 2011

Keywords

15-Lipoxygenase
15-S-HETE
Arachidonic acid metabolism
Free radicals
NF-κB
Prostate cancer
TGFβ2
Vitamin E
γ-Tocotrienol

ASJC Scopus subject areas

Biochemistry
Physiology (medical)

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10.1016/j.freeradbiomed.2011.02.007

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Campbell, S. E., Rudder, B., Phillips, R. B., Whaley, S. G., Stimmel, J. B., Leesnitzer, L. M., Lightner, J., Dessus-Babus, S., Duffourc, M., Stone, W. L., Menter, D. G., Newman, R. A., Yang, P., Aggarwal, B. B., & Krishnan, K. (2011). γ-Tocotrienol induces growth arrest through a novel pathway with TGFβ2 in prostate cancer. Free Radical Biology and Medicine, 50(10), 1344-1354. https://doi.org/10.1016/j.freeradbiomed.2011.02.007

Campbell, SE, Rudder, B, Phillips, RB, Whaley, SG, Stimmel, JB, Leesnitzer, LM, Lightner, J, Dessus-Babus, S, Duffourc, M, Stone, WL, Menter, DG, Newman, RA, Yang, P, Aggarwal, BB & Krishnan, K 2011, 'γ-Tocotrienol induces growth arrest through a novel pathway with TGFβ2 in prostate cancer', Free Radical Biology and Medicine, vol. 50, no. 10, pp. 1344-1354. https://doi.org/10.1016/j.freeradbiomed.2011.02.007

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title = "γ-Tocotrienol induces growth arrest through a novel pathway with TGFβ2 in prostate cancer",

abstract = "Regions along the Mediterranean and in southern Asia have lower prostate cancer incidence compared to the rest of the world. It has been hypothesized that one of the potential contributing factors for this low incidence includes a higher intake of tocotrienols. Here we examine the potential of γ-tocotrienol (GT3) to reduce prostate cancer proliferation and focus on elucidating pathways by which GT3 could exert a growth-inhibitory effect on prostate cancer cells. We find that the γ and δ isoforms of tocotrienol are more effective at inhibiting the growth of prostate cancer cell lines (PC-3 and LNCaP) compared with the γ and δ forms of tocopherol. Knockout of PPAR-γ and GT3 treatment show inhibition of prostate cancer cell growth, through a partially PPAR-γ-dependent mechanism. GT3 treatment increases the levels of the 15-lipoxygenase-2 enzyme, which is responsible for the conversion of arachidonic acid to the PPAR-γ-activating ligand 15-S-hydroxyeicosatrienoic acid. In addition, the latent precursor and the mature forms of TGFβ2 are down-regulated after treatment with GT3, with concomitant disruptions in TGFβ receptor I, SMAD-2, p38, and NF-κB signaling.",

keywords = "15-Lipoxygenase, 15-S-HETE, Arachidonic acid metabolism, Free radicals, NF-κB, Prostate cancer, TGFβ2, Vitamin E, γ-Tocotrienol",

author = "Campbell, {Sharon E.} and Brittney Rudder and Phillips, {Regenia B.} and Whaley, {Sarah G.} and Stimmel, {Julie B.} and Leesnitzer, {Lisa M.} and Janet Lightner and Sophie Dessus-Babus and Michelle Duffourc and Stone, {William L.} and Menter, {David G.} and Newman, {Robert A.} and Peiying Yang and Aggarwal, {Bharat B.} and Koyamangalath Krishnan",

note = "Funding Information: We thank our grant sponsors for this work: American Institute for Cancer Research ( 05A119-REV2 ), Department of Defense Program Exploration and Hypothesis Development Award PC030061, and Paul Dishner Chair of Excellence in Medicine Funding, East Tennessee State of University. We also thank W.H. Leong and David Ho at Carotech, Inc. (Edison, NJ, USA), for their generous supply of tocotrienols. We also thank the ETSU Molecular Core Facility for their help in designing our primers. A special thanks to Dr. V. Krishna K. Chatterjee, Department of Medicine, University of Cambridge (Cambridge, UK), who has supplied us and countless other scientists with the PPAR-γ dominant negative vector.",

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doi = "10.1016/j.freeradbiomed.2011.02.007",

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T1 - γ-Tocotrienol induces growth arrest through a novel pathway with TGFβ2 in prostate cancer

AU - Campbell, Sharon E.

AU - Rudder, Brittney

AU - Phillips, Regenia B.

AU - Whaley, Sarah G.

AU - Stimmel, Julie B.

AU - Leesnitzer, Lisa M.

AU - Lightner, Janet

AU - Dessus-Babus, Sophie

AU - Duffourc, Michelle

AU - Stone, William L.

AU - Menter, David G.

AU - Newman, Robert A.

AU - Yang, Peiying

AU - Aggarwal, Bharat B.

AU - Krishnan, Koyamangalath

N1 - Funding Information: We thank our grant sponsors for this work: American Institute for Cancer Research ( 05A119-REV2 ), Department of Defense Program Exploration and Hypothesis Development Award PC030061, and Paul Dishner Chair of Excellence in Medicine Funding, East Tennessee State of University. We also thank W.H. Leong and David Ho at Carotech, Inc. (Edison, NJ, USA), for their generous supply of tocotrienols. We also thank the ETSU Molecular Core Facility for their help in designing our primers. A special thanks to Dr. V. Krishna K. Chatterjee, Department of Medicine, University of Cambridge (Cambridge, UK), who has supplied us and countless other scientists with the PPAR-γ dominant negative vector.

PY - 2011/5/15

Y1 - 2011/5/15

N2 - Regions along the Mediterranean and in southern Asia have lower prostate cancer incidence compared to the rest of the world. It has been hypothesized that one of the potential contributing factors for this low incidence includes a higher intake of tocotrienols. Here we examine the potential of γ-tocotrienol (GT3) to reduce prostate cancer proliferation and focus on elucidating pathways by which GT3 could exert a growth-inhibitory effect on prostate cancer cells. We find that the γ and δ isoforms of tocotrienol are more effective at inhibiting the growth of prostate cancer cell lines (PC-3 and LNCaP) compared with the γ and δ forms of tocopherol. Knockout of PPAR-γ and GT3 treatment show inhibition of prostate cancer cell growth, through a partially PPAR-γ-dependent mechanism. GT3 treatment increases the levels of the 15-lipoxygenase-2 enzyme, which is responsible for the conversion of arachidonic acid to the PPAR-γ-activating ligand 15-S-hydroxyeicosatrienoic acid. In addition, the latent precursor and the mature forms of TGFβ2 are down-regulated after treatment with GT3, with concomitant disruptions in TGFβ receptor I, SMAD-2, p38, and NF-κB signaling.

AB - Regions along the Mediterranean and in southern Asia have lower prostate cancer incidence compared to the rest of the world. It has been hypothesized that one of the potential contributing factors for this low incidence includes a higher intake of tocotrienols. Here we examine the potential of γ-tocotrienol (GT3) to reduce prostate cancer proliferation and focus on elucidating pathways by which GT3 could exert a growth-inhibitory effect on prostate cancer cells. We find that the γ and δ isoforms of tocotrienol are more effective at inhibiting the growth of prostate cancer cell lines (PC-3 and LNCaP) compared with the γ and δ forms of tocopherol. Knockout of PPAR-γ and GT3 treatment show inhibition of prostate cancer cell growth, through a partially PPAR-γ-dependent mechanism. GT3 treatment increases the levels of the 15-lipoxygenase-2 enzyme, which is responsible for the conversion of arachidonic acid to the PPAR-γ-activating ligand 15-S-hydroxyeicosatrienoic acid. In addition, the latent precursor and the mature forms of TGFβ2 are down-regulated after treatment with GT3, with concomitant disruptions in TGFβ receptor I, SMAD-2, p38, and NF-κB signaling.

KW - 15-Lipoxygenase

KW - 15-S-HETE

KW - Arachidonic acid metabolism

KW - Free radicals

KW - NF-κB

KW - Prostate cancer

KW - TGFβ2

KW - Vitamin E

KW - γ-Tocotrienol

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γ-Tocotrienol induces growth arrest through a novel pathway with TGFβ2 in prostate cancer

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