c-Myc -: Induced chemosensitization is mediated by suppression of cyclin D1 expression and nuclear factor-κB activity in pancreatic cancer cells
c-Myc -: Induced chemosensitization is mediated by suppression of cyclin D1 expression and nuclear factor-κB activity in pancreatic cancer cells
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DOI：
10.1158/1078-0432.ccr-06-1844
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发表时间：
2007-05-01
影响因子：
11.5
通讯作者：
Liao, Joshua D.
中科院分区：
文献类型：
--
作者：
Biliran, Hector, Jr.;Banerjee, Sanjeev;Liao, Joshua D.
目的：胰腺癌是一种高度侵袭性的疾病，对各种化疗药物都很难治疗。由于原癌基因c-myc可以调节细胞凋亡的细胞毒性的侮辱，通常在胰腺癌中过度表达，我们研究的价值c-myc作为一个潜在的调制器的细胞反应各种化疗agents.Experimental设计：稳定的过度表达或小干扰RNA（siRNA）介导的敲低c-myc和恢复细胞周期蛋白D1在Ela-myc胰腺肿瘤细胞系。用3-（4，5-二甲基噻唑-2-基）-2，5-二苯基四唑溴化物测定c-myc过表达细胞、对照细胞和siRNA转染细胞顺铂处理后的细胞活力，用DNA片段化、亚G（1）和聚（ADP-核糖）聚合酶裂解分析测定药物诱导的细胞凋亡。结果：c-myc在小鼠胰腺癌细胞株Ela-myc和人胰腺癌细胞株L3.6pl中的异位过表达，分别导致细胞对顺铂和其他化疗药物的敏感性增加。c-myc过表达细胞对顺铂的敏感性增加，部分原因是顺铂诱导的细胞凋亡显著增加。相反，c-myc siRNA下调稳定的c-myc过表达细胞中的c-myc表达导致对顺铂诱导的细胞死亡的敏感性降低。这些结果表明c-myc在胰腺癌细胞的化疗敏感性中起重要作用。c-myc诱导的顺铂敏感性与抑制核因子κ B活性相关，这是部分恢复异位cyclin D1 overexpression.Conclusions：我们的研究结果表明，c-myc依赖敏化化疗诱导的细胞凋亡涉及抑制cyclin D1的表达和核因子κ B活性。
Purpose: Pancreatic cancer is a highly aggressive disease that remains refractory to various chemotherapeutic agents. Because the proto-oncogene c-myc can modulate apoptosis in response to cytotoxic insults and is commonly overexpressed in pancreatic cancer, we investigated the value of c-myc as a potential modulator of cellular response to various chemotherapeutic agents.Experimental Design: Stable overexpression or small interfering RNA (si RNA)-mediated knockdown of c-myc and restoration of cyclin D1 were done in the Ela-myc pancreatic tumor cell line. Cell viability after cisplatin treatment of c-myc-overexpressing, control, and siRNA-transfected cells was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and drug-induced apoptosis was measured by DNA fragmentation, sub-G(1), and poly (ADP-ribose) polymerase cleavage analyses. Protein expression profile after cisplatin treatment was determined by Western blotting and DNA binding activity of nuclear factor-kappa B was examined by electrophoretic mobility shift assay.Results: Ectopic overexpression of c-myc in murine and human pancreatic cancer cell lines, Ela-myc and L3.6pl, respectively, resulted in increased sensitivity to cisplatin and other chemotherapeutic drugs. Increased sensitivity to cisplatin in c-myc-overexpressing cells was due, in part, to the marked increase in cisplatin-induced apoptosis. Conversely, down-regulation of c-myc expression in stable c-myc-overexpressing cells by c-myc si RNA resulted in decreased sensitivity to cisplatin-induced cell death. These results indicate an important role of c-myc in chemosensitivity of pancreatic cancer cells. The c-myc-induced cisplatin sensitivity correlated with inhibition of nuclear factor kappa B activity, which was partially restored by ectopic cyclin D1 overexpression.Conclusions: Our results suggest that the c-myc-dependent sensitization to chemotherapy-induced apoptosis involves suppression of cyclin D1 expression and nuclear factor kappa B activity.