Tocopherol-associated protein suppresses prostate cancer cell growth by inhibition of the phosphoinositide 3-kinase pathway

Jing Ni, Xingqiao Wen, Jorge Yao, Hong Chiang Chang, Yi Yin, Min Zhang, Shaozhen Xie, Ming Chen, Brenna Simons, Philip Chang, Anthony Di Sant'Agnese, Edward M. Messing, Shuyuan Yeh

Research output: Contribution to journalArticle

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Abstract

Epidemiologic studies suggested that vitamin E has a protective effect against prostate cancer. We showed here that tocopherol-associated protein (TAP), a vitamin E-binding protein, promoted vitamin E uptake and facilitated vitamin E antiproliferation effect in prostate cancer cells. Interestingly, without vitamin E treatment, overexpression of TAP in prostate cancer cells significantly suppressed cell growth; knockdown of endogenous TAP by TAP small interfering RNA (siRNA) in nonmalignant prostate HPr-1 cells increased cell growth. Further mechanism dissection studies suggested that the tumor suppressor function of TAP was via down-regulation of phosphoinositide 3-kinase (PI3K)/Akt signaling, but not by modulating cell cycle arrest or androgen receptor signaling. Immunoprecipitation results indicated that TAP inhibited the interaction of PI3K subunits, p110 with p85, and subsequently reduced Akt activity. Constitutively active Akt could negate the TAP-suppressive activity on prostate cancer cell growth. Moreover, stable transfection of TAP in LNCaP cells suppressed LNCaP tumor incidence and growth rate in nude mice. Furthermore, TAP mRNA and protein expression levels were significantly down-regulated in human prostate cancer tissue samples compared with benign prostate tissues as measured by reverse transcription-PCR, in situ hybridization, and immunohistochemistry. Together, our data suggest that TAP not only mediates vitamin E absorption to facilitate vitamin E antiproliferation effect in prostate cancer cells, but also functions like a tumor suppressor gene to control cancer cell viability through a non-vitamin E manner. Therefore, TAP may represent a new prognostic marker for prostate cancer progression.

Original languageEnglish (US)
Pages (from-to)9807-9816
Number of pages10
JournalCancer Research
Volume65
Issue number21
DOIs
StatePublished - Nov 1 2005

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1-Phosphatidylinositol 4-Kinase
Tocopherols
Prostatic Neoplasms
Vitamin E
Growth
Proteins
Prostate
Neoplasms
Androgen Receptors
Cell Cycle Checkpoints
Tumor Suppressor Genes
Immunoprecipitation
Nude Mice
Small Interfering RNA
Reverse Transcription
In Situ Hybridization
Transfection
Dissection
Epidemiologic Studies
Cell Survival

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Tocopherol-associated protein suppresses prostate cancer cell growth by inhibition of the phosphoinositide 3-kinase pathway. / Ni, Jing; Wen, Xingqiao; Yao, Jorge; Chang, Hong Chiang; Yin, Yi; Zhang, Min; Xie, Shaozhen; Chen, Ming; Simons, Brenna; Chang, Philip; Di Sant'Agnese, Anthony; Messing, Edward M.; Yeh, Shuyuan.

In: Cancer Research, Vol. 65, No. 21, 01.11.2005, p. 9807-9816.

Research output: Contribution to journalArticle

Ni, J, Wen, X, Yao, J, Chang, HC, Yin, Y, Zhang, M, Xie, S, Chen, M, Simons, B, Chang, P, Di Sant'Agnese, A, Messing, EM & Yeh, S 2005, 'Tocopherol-associated protein suppresses prostate cancer cell growth by inhibition of the phosphoinositide 3-kinase pathway', Cancer Research, vol. 65, no. 21, pp. 9807-9816. https://doi.org/10.1158/0008-5472.CAN-05-1334
Ni, Jing ; Wen, Xingqiao ; Yao, Jorge ; Chang, Hong Chiang ; Yin, Yi ; Zhang, Min ; Xie, Shaozhen ; Chen, Ming ; Simons, Brenna ; Chang, Philip ; Di Sant'Agnese, Anthony ; Messing, Edward M. ; Yeh, Shuyuan. / Tocopherol-associated protein suppresses prostate cancer cell growth by inhibition of the phosphoinositide 3-kinase pathway. In: Cancer Research. 2005 ; Vol. 65, No. 21. pp. 9807-9816.
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AU - Yin, Yi

AU - Zhang, Min

AU - Xie, Shaozhen

AU - Chen, Ming

AU - Simons, Brenna

AU - Chang, Philip

AU - Di Sant'Agnese, Anthony

AU - Messing, Edward M.

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AB - Epidemiologic studies suggested that vitamin E has a protective effect against prostate cancer. We showed here that tocopherol-associated protein (TAP), a vitamin E-binding protein, promoted vitamin E uptake and facilitated vitamin E antiproliferation effect in prostate cancer cells. Interestingly, without vitamin E treatment, overexpression of TAP in prostate cancer cells significantly suppressed cell growth; knockdown of endogenous TAP by TAP small interfering RNA (siRNA) in nonmalignant prostate HPr-1 cells increased cell growth. Further mechanism dissection studies suggested that the tumor suppressor function of TAP was via down-regulation of phosphoinositide 3-kinase (PI3K)/Akt signaling, but not by modulating cell cycle arrest or androgen receptor signaling. Immunoprecipitation results indicated that TAP inhibited the interaction of PI3K subunits, p110 with p85, and subsequently reduced Akt activity. Constitutively active Akt could negate the TAP-suppressive activity on prostate cancer cell growth. Moreover, stable transfection of TAP in LNCaP cells suppressed LNCaP tumor incidence and growth rate in nude mice. Furthermore, TAP mRNA and protein expression levels were significantly down-regulated in human prostate cancer tissue samples compared with benign prostate tissues as measured by reverse transcription-PCR, in situ hybridization, and immunohistochemistry. Together, our data suggest that TAP not only mediates vitamin E absorption to facilitate vitamin E antiproliferation effect in prostate cancer cells, but also functions like a tumor suppressor gene to control cancer cell viability through a non-vitamin E manner. Therefore, TAP may represent a new prognostic marker for prostate cancer progression.

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