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
Department of Urology, University of Rochester, Rochester, New York, USA.
Cancer Res. 2005 Nov 1;65(21):9807-16. doi: 10.1158/0008-5472.CAN-05-1334.
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.
流行病学研究表明，维生素E对前列腺癌具有保护作用。我们在此表明，生育酚相关蛋白（TAP），一种维生素E结合蛋白，可促进维生素E摄取并增强其在前列腺癌细胞中的抗增殖作用。有趣的是，在未进行维生素E处理的情况下，前列腺癌细胞中TAP的过表达显著抑制细胞生长；在非恶性前列腺HPr-1细胞中，通过TAP小干扰RNA（siRNA）敲低内源性TAP可增加细胞生长。进一步的机制剖析研究表明，TAP的肿瘤抑制功能是通过下调磷酸肌醇3激酶（PI3K）/Akt信号通路实现的，而非通过调节细胞周期阻滞或雄激素受体信号通路。免疫沉淀结果表明，TAP抑制PI3K亚基p110与p85的相互作用，进而降低Akt活性。组成型活性Akt可抵消TAP对前列腺癌细胞生长的抑制活性。此外，在LNCaP细胞中稳定转染TAP可抑制裸鼠体内LNCaP肿瘤的发生率和生长速率。此外，通过逆转录PCR、原位杂交和免疫组织化学检测发现，与良性前列腺组织相比，人前列腺癌组织样本中TAP mRNA和蛋白表达水平显著下调。总之，我们的数据表明，TAP不仅介导维生素E吸收以促进其在前列腺癌细胞中的抗增殖作用，还作为一种肿瘤抑制基因，通过非维生素E的方式控制癌细胞活力。因此，TAP可能是前列腺癌进展的一种新的预后标志物。
