新功能、新界面、新体验,扫描即可下载生物谷APP!
首页 » 保护胰脏癌细胞免于凋亡的蛋白质

保护胰脏癌细胞免于凋亡的蛋白质

来源:华文生技网 2007-03-30 09:25

    胰导管腺癌是恶性程度最大的肿瘤疾病之一,而且相当难治疗。美国德州大学M.D. Anderson癌症中心的研究人员发现一种过度表现的蛋白质,会保护人类的胰脏癌细胞免受身体控制细胞生长的自然防御机制-自噬作用而死亡。

    这项研究结果发表于3月号的Molecular Cancer Research中。研究人员之前发现一些耐药性和转移的肿瘤和肿瘤细胞株中,会表现转谷氨酰胺酶(TG2)。研究作者Kapil Mehta去年和同事发现,TG2过度表现与抗药性和转移的乳癌、胰脏癌和黑色素瘤有关。正常细胞中很少见到TG2的表现。

    TG2在健康细胞受到严格的调控,只有在回应某些激素或紧迫因素时,才会暂时增加。然而,这种蛋白质表现于癌细胞中,可保护它们免于细胞凋亡。TG2可以促进肿瘤的药物抗性,且逃避体内侦测癌细胞转移的机制。

    研究人员以二种不同方式抑制实验中胰脏癌细胞的TG2表现。首先,研究人员阻拦了其它已知会活化TG2的蛋白质。接着,他们直接利用iRNA瞄准TG2。结果发现胰脏癌细胞发生细胞自噬。

    研究人员认为未来可以瞄准TG2或它活化的蛋白质PKC,而作为有效的胰脏癌疗法,目前他们正在努力朝着动物研究迈进。

    (资料来源 : Bio.com)

Molecular Cancer Research 5, 241-249, March 1, 2007. doi: 10.1158/1541-7786.MCR-06-0229

Signaling and Regulation

Tissue Transglutaminase Inhibits Autophagy in Pancreatic Cancer Cells

Ugur Akar1, Bulent Ozpolat1, Kapil Mehta1, Jansina Fok1, Yasuko Kondo2 and Gabriel Lopez-Berestein1

Departments of 1 Experimental Therapeutics and 2 Neurosurgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Gabriel Lopez-Berestein, Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Unit 422, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-792-8140; Fax: 713-796-1731. E-mail: glopez@mdanderson.org

Elevated expression of tissue transglutaminase (TG2) in cancer cells has been implicated in the development of drug resistance and metastatic phenotypes. However, the role and the mechanisms that regulate TG2 expression remain elusive. Here, we provide evidence that protein kinase C (PKC) regulates TG2 expression, which in turn inhibits autophagy, a type II programmed cell death, in pancreatic cancer cells that are frequently insensitive to standard chemotherapeutic agents. Rottlerin, a PKC-specific inhibitor, and PKC small interfering RNA (siRNA) down-regulated the expression of TG2 mRNA and protein and induced growth inhibition without inducing apoptosis in pancreatic cancer cells. Inhibition of PKC by rottlerin or knockdown of TG2 protein by a TG2-specific siRNA resulted in a marked increase in autophagy shown by presence of autophagic vacuoles in the cytoplasm, formation of the acidic vesicular organelles, membrane association of microtubule-associated protein 1 light chain 3 (LC3) with autophagosomes, and a marked induction of LC3-II protein, important hallmarks of autophagy, and by electron microscopy. Furthermore, inhibition of TG2 by rottlerin or by the siRNA led to accumulation of green fluorescent protein (GFP)-LC3-II in autophagosomes in pancreatic cancer cells transfected with GFP-LC3 (GFP-ATG8) expression vector. Knockdown of Beclin-1, a specific autophagy-promoting protein and the product of Becn1 (ATG6), inhibited rottlerin-induced and TG2 siRNA–induced autophagy, indicating that Beclin-1 is required for this process. These results revealed that PKC plays a critical role in the expression of TG2, which in turn regulates autophagy. In conclusion, these results suggest a novel mechanism of regulation of TG2 and TG2-mediated autophagy in pancreatic cancer cells. (Mol Cancer Res 2007;5(3):241–9)

相关报道:

胰脏癌中异常表现的microRNA有助于新诊断方法的研发

可能是单一基因启动了癌细胞的转变

Nature:科学家发现细胞衰老的一般机制

温馨提示:87%用户都在生物谷APP上阅读,扫描立刻下载! 天天精彩!


相关标签

最新会议 培训班 期刊库