Thioredoxin Inhibition of Apoptosis and Cancer Treatment

超出提供的空间。抵抗正常调节的细胞死亡(细胞凋亡)是癌症表型的特征之一。逃脱凋亡使癌细胞能够在低氧、高酸度和营养供应有限的条件下生长，就像生长中的肿瘤中发现的那样，正常细胞无法存活。这也解释了癌细胞对放射和化疗的内在抵抗力。了解癌细胞对凋亡产生抵抗力的机制，对于开发治疗癌症和克服耐药性的新疗法至关重要。硫氧还蛋白(Trxs)是一种小分子氧化还原蛋白，可被黄素蛋白硫氧还蛋白还原酶进行可逆的NADPH还原。人类有两个Trx，一个是细胞质的Trx-1，一个是线粒体的Trx-2。TRX-1可以转化正常细胞，刺激细胞生长，并对多种抗癌药物的凋亡产生明显的抵抗作用。TRX-1在许多人类原发肿瘤中高表达，与肿瘤侵袭性生长、自发性细胞凋亡减少和患者生存期减少有关。Trx-I抑制细胞凋亡的机制(S)尚不清楚。我们已经证明，TRX-1结合并抑制肿瘤抑制蛋白PTEN的活性，PTEN是磷脂酰肌醇-3-激酶/Akt细胞生存信号通路的脂质磷酸酶抑制剂。Trx-1还减少了Noxa的表达，Noxa是P53依赖的细胞凋亡的调节因子。我们提出了新的证据，TRX-2保护线粒体免受氧化损伤，并可能保护癌细胞免受线粒体介导的凋亡。这些研究的基础假设是：Trx-1通过抑制磷脂酰肌醇-3-激酶/Akt细胞存活通路的失活和P53介导的细胞凋亡而发挥关键作用；而Trx-2通过保护线粒体损伤而发挥关键作用。此外，我们认为Trx的拮抗剂可以阻断这些抗细胞凋亡的作用，是一种有效的抗肿瘤药物。我们将使用TRX-1抑制剂PX-12和我们已经确定的两种新型TRX-1抑制剂。我们研究的目的是探讨TRX抑制细胞凋亡的机制，并开发我们已确定的潜在的癌症治疗药物。市、州)表演网站========================================Section End===========================================

EXCEED THE SPACE PROVIDED. Resistance to normal regulated cell death (apoptosis) is one of the characteristics of the cancer phenotype. Escape from apoptosis allows cancer cells to grow under conditions of low oxygen, high acidity and limited nutrient supply such as are found in the growing tumor where normal cells cannot survive. It also explains the intrinsic resistance of cancer cells to radiation and chemotherapy. Understanding the mechanisms by which cancer cells become resistant to apoptosis is central to the development of new therapies for the treatment of cancer and for overcoming drug resistance. Thioredoxins (Trxs) are small redox proteins that undergoes reversible NADPH- dependent reduction by flavoprotein thioredoxin reductases. There are two human Trxs, a cytosolic Trx-1 and a mitochondrial Trx-2. Trx-1 transforms normal cells, stimulates cell growth and causes a marked resistance to apoptosis by a variety of anticancer drugs. Trx-1 is over expressed in many human primary tumors where it is associated with aggressive tumor growth, decreased spontaneous apoptosis and with decreased patient survival. The mechanism(s) by which Trx-I inhibits apoptosis is not known. We have shown that Trx-1 binds to and represses the activity of the tumor suppresser protein PTEN, a lipid phosphatase inhibitor of the phosphatidyinositol-3-kinase/Akt cell survival signaling pathway. Trx-1 also decreases the expression ofNoxa a regulator ofp53-dependent apoptosis. We present new evidence that Trx-2 protects mitochondria against oxidant damage and may protect cancer cells against mitochondrial mediated apoptosis. The hypothesis upon which the proposed studies are based is that the Trxs play a critical role in preventing apoptosis in cancer cells; Trx-1 by inactivation of the phosphatidyinositol-3-kinase/Akt cell survival pathway and p53-mediated apoptosis; and Trx-2 by protection against mitochondrial damage. Furthermore, we propose that inl_bitors of Trx will block these antiapoptotic effects and will be effective antitumor agents. We will use the Trx-1 inhibitor PX-12 and two novel Trx-1 inhibitors we have identified. The objective of our studies is to investigate mechanisms for Trx inhibition of apoptosis and develop novel inhibitors of Trx we have identified as potential agents for the treatment of cancer. city, state) PERFORMANCE SITE ========================================Section End===========================================