胰導(dǎo)管腺癌是惡性程度最大的腫瘤疾病之一,，而且相當難治療,。美國德州大學(xué)M.D. Anderson癌癥中心的研究人員發(fā)現(xiàn)一種過度表現(xiàn)的蛋白質(zhì)，會保護人類的胰臟癌細胞免受身體控制細胞生長的自然防御機制-自噬作用而死亡,。
這項研究結(jié)果發(fā)表于3月號的Molecular Cancer Research中,。研究人員之前發(fā)現(xiàn)一些耐藥性和轉(zhuǎn)移的腫瘤和腫瘤細胞株中，會表現(xiàn)轉(zhuǎn)谷氨酰胺酶（TG2）,。研究作者Kapil Mehta去年和同事發(fā)現(xiàn),，TG2過度表現(xiàn)與抗藥性和轉(zhuǎn)移的乳癌、胰臟癌和黑色素瘤有關(guān),。正常細胞中很少見到TG2的表現(xiàn),。
TG2在健康細胞受到嚴格的調(diào)控，只有在回應(yīng)某些激素或緊迫因素時,，才會暫時增加,。然而，這種蛋白質(zhì)表現(xiàn)于癌細胞中,，可保護它們免于細胞凋亡。TG2可以促進腫瘤的藥物抗性,，且逃避體內(nèi)偵測癌細胞轉(zhuǎn)移的機制,。
研究人員以二種不同方式抑制實驗中胰臟癌細胞的TG2表現(xiàn)。首先,，研究人員阻攔了其它已知會活化TG2的蛋白質(zhì),。接著，他們直接利用iRNA瞄準TG2,。結(jié)果發(fā)現(xiàn)胰臟癌細胞發(fā)生細胞自噬,。
研究人員認為未來可以瞄準TG2或它活化的蛋白質(zhì)PKC，而作為有效的胰臟癌療法,，目前他們正在努力朝著動物研究邁進,。
(資料來源 : 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: [email protected]
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)
