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果膠誘導(dǎo)人前列腺癌細(xì)胞凋亡：果膠結(jié)構(gòu)與誘導(dǎo)細(xì)胞凋亡功能的相關(guān)性

作者：Crystal L Jackson2,3, Tina M Dreaden2,3, LisaK Theobald2,3, Nhien M Tran2,3, Tiffany L Beal2,3,Manal Eid4, Mu Yun Gao2,3, Robert B Shirley4, Mark T Stoffel2,3, M Vijay Kumar4, and Debra Mohnen1,2,3

復(fù)合碳水化合物研究中心和生物化學(xué)與分子生物學(xué)系，佐治亞大學(xué)，雅典，GA 30602和佐治亞醫(yī)學(xué)院和VA醫(yī)學(xué)中心，奧古斯塔，GA 30912

雄激素非依賴性前列腺癌細(xì)胞的治療選擇是有限的。因此，發(fā)現(xiàn)誘導(dǎo)雄激素反應(yīng)性和雄激素不敏感細(xì)胞凋亡的藥劑至關(guān)重要。在這里，我們驗(yàn)證一種來(lái)自植物細(xì)胞壁的成分果膠能夠誘導(dǎo)雄激素響應(yīng)（LNCaP）和雄激素非依賴性（LNCaP C4-2）人前列腺癌細(xì)胞的細(xì)胞凋亡。通過(guò)Apoptosense測(cè)定和胱天蛋白酶-3及其底物，聚（ADP-核糖）聚合酶的激活，市場(chǎng)上能買(mǎi)到的的分級(jí)果膠粉（FPP）在兩種細(xì)胞系中誘導(dǎo)細(xì)胞凋亡（比未處理的細(xì)胞高約40倍）。相反，柑橘果膠（CP）和經(jīng)pH調(diào)整的 CP，PectaSol，幾乎沒(méi)有細(xì)胞凋亡活性。糖基殘基組成和連鎖分析顯示果膠之間沒(méi)有顯著差異。用于除去酯鍵的溫和堿​​處理破壞了FPP的細(xì)胞凋亡活性并產(chǎn)生了高聚半乳糖醛酸（HG）寡糖。用果膠甲基酯酶處理FPP以去除半乳糖醛酸羧基甲基酯和/或用內(nèi)部多聚半乳糖酶來(lái)切割非甲基化的HG，導(dǎo)致細(xì)胞凋亡活性沒(méi)有顯著降低，這表明需要除羧甲基酯之外的堿敏感連接。 CP（HTCP）的熱處理導(dǎo)致誘導(dǎo)與FPP相當(dāng)?shù)娘@著水平的凋亡，揭示了生產(chǎn)一種具有凋亡能力的果膠結(jié)構(gòu)的手段。這些結(jié)果表明，果膠中的特定結(jié)構(gòu)元素是細(xì)胞凋亡活性的原因，并且這種結(jié)構(gòu)可以通過(guò)CP的熱處理產(chǎn)生或富集。這些發(fā)現(xiàn)為果膠凋亡活性的機(jī)理研究奠定了基礎(chǔ)，并為開(kāi)發(fā)基于果膠的藥物，營(yíng)養(yǎng)保健品或旨在對(duì)抗前列腺癌發(fā)生的推薦飲食改變奠定了基礎(chǔ)。

關(guān)鍵詞：細(xì)胞凋亡/癌癥/果膠/前列腺/結(jié)構(gòu)

Pectin induces apoptosis in human prostate cancer cells: correlation of apoptotic function with pectin structure

Crystal L Jackson2,3, Tina M Dreaden2,3, LisaK Theobald2,3, Nhien M Tran2,3, Tiffany L Beal2,3,Manal Eid4, Mu Yun Gao2,3, Robert B Shirley4, Mark
T Stoffel2,3, M Vijay Kumar4, and Debra Mohnen1,2,3
2 3
  Complex Carbohydrate Research Center and Department of Biochemistry and Molecular Biology, The University of Georgia, Athens, GA 30602 and
4
Medical College of Georgia and VA Medical Center, Augusta, GA 30912
Received on September 26, 2006; revised on May 9, 2007; accepted on May 11, 2007
Treatment options for androgen-independent prostate cancer cells are limited. Therefore, it is critical to identify agents that induce death of both androgen-responsive and androgen-insensitive cells. Here we demonstrate that a product of plant cell walls, pectin, is capable of inducing apoptosis in androgen-responsive (LNCaP) and androgen- independent (LNCaP C4-2) human prostate cancer cells. Commercially available fractionated pectin powder (FPP)induced apoptosis (approximately 40-fold above non- treated cells) in both cell lines as determined by the Apoptosense assay and activation of caspase-3 and its sub- strate, poly(ADP-ribose) polymerase. Conversely, citrus pectin (CP) and the pH-modified CP, PectaSol, had little or no apoptotic activity. Glycosyl residue composition and linkage analyses revealed no significant differences among the pectins. Mild base treatment to remove ester linkages destroyed FPP’s apoptotic activity and yielded homogalacturonan (HG) oligosaccharides. The treatment of FPP with pectinmethylesterase to remove galacturono- syl carboxymethylesters and/or with endopolygalacturo- nase to cleave nonmethylesterified HG caused no major reduction in apoptotic activity, implicating the requirement for a base-sensitive linkage other than the carboxymethyl- ester. Heat treatment of CP (HTCP) led to the induction of significant levels of apoptosis comparable to FPP, suggesting a means for generating apoptotic pectic struc- tures. These results indicate that specific structural elements within pectin are responsible for the apoptotic activity, and that this structure can be generated, or enriched for, by heat treatment of CP. These findings provide the foundation for mechanistic studies of pectin apoptotic activity and a basis for the development of pectin- based pharmaceuticals, nutraceuticals, or recommended diet changes aimed at combating prostate cancer occurrence
and progression.
Key words: apoptosis/cancer/pectin/prostate/structure