• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文学位 >Chemopreventive and chemotherapeutic mechanisms of sphingolipid metabolites in human colon cancer cells and breast stem, normal, and tumorigenic cells.
【24h】

Chemopreventive and chemotherapeutic mechanisms of sphingolipid metabolites in human colon cancer cells and breast stem, normal, and tumorigenic cells.

机译：人结肠癌细胞和乳腺干细胞，正常细胞和致瘤细胞中鞘脂代谢物的化学预防和化学治疗机制。

获取原文
获取原文并翻译 | 示例
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

The effects of the sphingolipid metabolites (sphingosine, sphinganine, ceramide, and dihydroceramide) on proliferation and differentiation in human normal epithelial cells versus tumorigenic cells and stem cells have not previously been compared. This dissertation research addressed these questions using following cell culture models: HT-29 and HCT-116 human colon cancer epithelial cells, human breast epithelial cells (HBEC) developed from tissues of healthy women obtained during reduction mammoplasty (type I HBEC with stem cell characteristics as target cells for breast carcinogenesis and type II HBEC with basal epithelial cell phenotypes as breast normal cells) and transformed tumorigenic type I HBEC as breast cancer cells.; The objectives of the present study were to: (1) investigate the effects of sphingoid bases (sphingosine and sphinganine), ceramide, and dihydroceramide on proliferation, cell cycle, and apoptosis of HT-29 and HCT-116 cells; (2) determine the effects of sphinganine on major isoforms of mitogen activated protein kinases (ERK, JNK, and p38) and AKT (protein kinase B) in HT-29 cells; (3) evaluate the effects of sphingoid bases on proliferation, cell cycle, and apoptosis of tumorigenic type I HBEC and type I HBEC compared to type II HBEC; and (4) determine the effects of sphingoid bases on the ability of type I HBEC to differentiate to type II HBEC.; Data from HT-29 and HCT-116 cells indicate that sphingoid bases and C 2-ceramide at 20–50 μM inhibited the growth, arrested cell cycle at G2/M phase, and induced apoptosis, with sphinganine being the most potent of the metabolites studied. In contrast, C2-dihydroceramide had no effect, suggesting that the 4,5-trans double bond is necessary for the inhibitory effects of C2-ceramide, but not for inhibitory effects of sphingoid bases. Sphinganine at an apoptosis-inducing concentration (35 μM) caused early and strong activation of JNK2/JNK1 and p38 and early inhibition of AKT, with minimal effects on activation of ERK1/ERK2 in HT-29 cells.; Results from HBEC show that sphinganine more potently inhibited the growth and induced apoptosis of tumorigenic type I HBEC than sphingosine (IC 50 for sphinganine 4 μM; sphingosine 6.4 μM). Sphingoid bases (8–10 μM) arrested cell cycle at G2/M with reductions in S and G0/G1 phases. Sphinganine also more potently inhibited the growth and caused death of type I HBEC than sphingosine, while the same concentrations of both sphinganine and sphingosine had minor effects on type II HBEC. At concentrations (0.05–0.5μM), which are below the growth inhibitory range, sphingoid bases induced differentiation of type I HBEC to type II HBEC, as detected with concomitant expression of the novel tumor suppressor protein, maspin, in type II HBEC.; In conclusion, sphingoid bases and ceramide might possess chemotherapeutic properties against colon cancer, with sphinganine being the most potent. Activation of JNK and p38 and inhibition of AKT might mediate sphinganine-induced apoptosis of colon cancer cells. Data indicate the potential for sphingoid bases to be employed as chemotherapeutic and chemopreventive agents against human breast cancer.
机译：鞘脂代谢物（鞘氨醇，鞘氨醇，神经酰胺和二氢神经酰胺）对人正常上皮细胞相对于致瘤细胞和干细胞的增殖和分化的影响以前没有被比较过。本论文的研究使用以下细胞培养模型解决了这些问题：HT-29和HCT-116人结肠癌上皮细胞，从乳腺成形术中获得的健康女性组织（具有干细胞特征的I型HBEC）发展而来的人乳腺上皮细胞（HBEC）作为乳腺癌致癌和II型HBEC的靶细胞，以基底上皮细胞表型作为乳腺癌正常细胞）和转化的致瘤性I型HBEC作为乳腺癌细胞。本研究的目的是：（1）研究鞘氨醇碱（鞘氨醇和鞘氨醇），神经酰胺和二氢神经酰胺对HT-29和HCT-116细胞的增殖，细胞周期和细胞凋亡的影响; （2）确定Sphinganine对HT-29细胞中丝裂原活化蛋白激酶（ERK，JNK和p38）和AKT（蛋白激酶B）的主要同工型的影响; （3）与第二型HBEC相比，评估鞘氨醇碱基对致瘤性I型HBEC和I型HBEC增殖，细胞周期和凋亡的影响; （4）确定类鞘氨醇对I型HBEC分化为II型HBEC的能力的影响; HT-29和HCT-116细胞的数据表明，鞘氨醇碱和20–50μM的C 2 -神经酰胺抑制了G 2 / M的生长和停滞的细胞周期阶段，并诱导了细胞凋亡，其中狮身人面像是研究的最有效的代谢产物。相反，C 2 -二氢神经酰胺没有作用，表明4,5- trans 双键对于C 2 -神经酰胺，但不适用于鞘氨醇碱的抑制作用。 Sphinganine以凋亡诱导浓度（35μM）引起JNK2 / JNK1和p38的早期和强活化，以及AKT的早期抑制，而对HT-29细胞中ERK1 / ERK2的活化影响最小。 HBEC的结果表明，与鞘氨醇相比，Sphinganine更有效地抑制了I型HBEC的生长并诱导了其凋亡（鞘氨醇4μM，IC 50 ；鞘氨醇6.4μM，IC 50 ）。鞘氨醇碱基（8–10μM）使细胞周期停滞在G 2 / M，S和G 0 / G 1 期减少。与鞘氨醇相比，Sphinganine还更有效地抑制I型HBEC的生长并导致IHBEC死亡，而相同浓度的Sphinganine和鞘氨醇对II型HBEC的影响较小。在低于生长抑制范围的浓度（0.05-0.5μM）下，鞘氨醇碱基诱导了I型HBEC向II型HBEC的分化，这与新型肿瘤抑制蛋白maspin在II型HBEC中的伴随表达相吻合。总之，鞘氨醇碱和神经酰胺可能具有抗结肠癌的化学治疗特性，其中狮身人面像是最有效的。 JNK和p38的激活和AKT的抑制可能介导鞘氨醇诱导的结肠癌细胞凋亡。数据表明鞘氨醇碱可用作抗人乳腺癌的化学治疗剂和化学预防剂的潜力。

著录项

  • 作者

    Ahn, Eun Hyun.;

  • 作者单位

    Michigan State University.;

  • 授予单位 Michigan State University.;
  • 学科 Health Sciences Nutrition.; Biology Molecular.; Health Sciences Oncology.
  • 学位 Ph.D.
  • 年度 2003
  • 页码 212 p.
  • 总页数 212
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 预防医学、卫生学;分子遗传学;肿瘤学;
  • 关键词

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号