Predominant Bcl-XL knockdown disables antiapoptotic mechanisms:: Tumor necrosis factor-related apoptosis-inducing ligand-based triple chemotherapy overcomes chemoresistance in pancreatic cancer cells in vitro
Predominant Bcl-XL knockdown disables antiapoptotic mechanisms:: Tumor necrosis factor-related apoptosis-inducing ligand-based triple chemotherapy overcomes chemoresistance in pancreatic cancer cells in vitro
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DOI：
10.1158/0008-5472.can-04-3502
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发表时间：
2005-03-15
期刊：
影响因子：
11.2
通讯作者：
Callery, MP
中科院分区：
文献类型：
--
作者：
Bai, JR;Sui, JH;Callery, MP
胰腺癌是致命的，因为它的侵袭性，进展迅速，以及对化疗和放射治疗的严重抵抗。为了确定这一现象的分子机制，我们检测了三种主要的死亡受体：肿瘤坏死因子受体(TNF-R)、肿瘤坏死因子相关的凋亡诱导配体受体(TRAIL-R)和Fas在四种侵袭性胰腺癌细胞系中的表达和活性。我们分析了主要的抗凋亡因子、细胞周期调节因子和死亡受体诱骗(DCR)的表达，并与正常胰腺组织和其他五种人类恶性肿瘤细胞系进行了比较。我们发现，不同的胰腺癌细胞株共表达高水平的TRAIL-R、Fas和TNF-R1，但对死亡受体引发的细胞凋亡具有很强的抵抗力。DcR2和DcR3的过表达可能部分参与了胰腺癌细胞对TRAIL-R和Fas介导的细胞毒作用的抵抗。BCI-XL和BCI-2分别在胰腺癌细胞系中过表达。BCL-XL也主要在前列腺癌、结直肠癌细胞和肠道癌细胞中过表达。抗肿瘤药物格尔达霉素、PS-341、曲古抑素A和阿霉素亚致死剂量可显著降低胰腺癌细胞对肿瘤坏死因子α和TRAIL介导的细胞凋亡的抑制作用。格尔达那霉素和PS-341协同阻断NF-kappaB的激活，抑制Akt/PKB通路，下调Bclxl、Bcl2、CIAP-1和细胞周期蛋白D1的表达。这种联合方案极大地增强了TRAIL的细胞毒作用，并突破了化疗耐药性。Bclxl在胰腺癌化疗耐药中起重要作用。格尔达霉素、PS-341和TRAIL三联疗法可能成为治疗胰腺癌的新策略。
Pancreatic cancer is lethal because of its invasiveness, rapid progression, and profound resistance to chemotherapy and radiation therapy. To identify the molecular mechanisms underlying this, we have examined the expression and potency of three major death receptors: tumor necrosis factor receptor (TNF-R), TNF-related apoptosis-inducing ligand receptor (TRAIL-R), and Fas in mediating cytotoxicity in four invasive pancreatic cancer cell lines. We have analyzed the expression of major antiapoptotic factors, cell cycle regulators and death receptor decoys (DcR) in comparison with normal pancreas tissues and five other human malignant tumor cell lines. We have found that different pancreatic cancer cell lines coexpress high-level TRAIL-R, Fas, and TNF-R1 but are strongly resistant to apoptosis triggered by the death receptors. DcR2 and DcR3 overexpression may partly contribute to the resistance of pancreatic cancer cells to TRAIL-R- and Fas-mediated cytotoxicity. BcI-XL and BcI-2 are predominantly overexpressed in pancreatic cancer cell lines, respectively. Bcl-XL is also predominantly overexpressed in prostate, colorectal, and intestinal cancer cells. The knockdown of the predominant Bcl-XL overexpression significantly reduces the viability of pancreatic cancer cells to TNF alpha- and TRAIL-mediated apoptosis by sublethal-dose single and combined antitumor drugs, including geldanamycin, PS-341, Trichostatin A, and doxorubicine. Geldanamyin and PS-341 synergistically block NF kappa B activation, suppress Akt/PKB pathway, and down-regulate Bcl-XL, Bcl-2, cIAP-1, and cyclin D1 expression. This combined regimen dramatically enhances TRAIL cytotoxic effects and breaks through chemoresistance. Bcl-XL plays a vital role in pancreatic cancer chemoresistance. Geldanamycin, PS-341, and TRAIL triple combination may be a novel therapeutic strategy for pancreatic cancer.