PKCalpha-induced drug resistance in pancreatic cancer cells is associated with transforming growth factor-beta1.
PKCalpha-induced drug resistance in pancreatic cancer cells is associated with transforming growth factor-beta1.
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DOI：
10.1186/1756-9966-29-104
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发表时间：
2010-08-05
期刊：
影响因子：
--
通讯作者：
Zhu M
中科院分区：
文献类型：
--
作者：
Chen Y;Yu G;Yu D;Zhu M
耐药仍然是胰腺癌治疗中的一个巨大挑战。本研究的目的是确定TGF-β 1是否与胰腺癌的耐药性相关。用TGF-β 1 cDNA稳定转染胰腺癌BxPC 3细胞。采用抑制性消减杂交（SSH）技术检测TGF-β 1诱导的细胞形态学和细胞周期变化，筛选差异表达基因。采用Western blotting和免疫组织化学方法检测TGF-β 1相关基因在细胞和组织中的表达。之后，用抗癌药物（例如，顺铂）与重组TGF-β 1加PKC α抑制剂Gö6976预孵育后。用T β RII siRNA敲除TGF-β 1II型受体T β RII，观察药物对细胞的作用。MTT法检测细胞活力。TGF-β 1的过表达导致BxPC 3细胞的侵袭潜力显着增加，但生长速率降低。重组TGF-β 1蛋白可增加BxPC 3细胞PKC α的表达，抑制消减杂交证实了这一结果。TGF-β 1可降低BxPC 3细胞对顺铂的敏感性，其机制可能与PKC α表达上调有关。然而，用Gö6976阻断PKC α和用siRNA阻断T β RII逆转了BxPC 3细胞对吉西他滨的耐药性，即使在存在TGF-β 1的情况下也是如此。免疫组化数据显示，胰腺癌相对于正常组织过度表达TGF-β 1和P-gp。此外，胰腺癌组织中TGF-β 1的表达与P-gp和膜PKC α的表达相关。TGF-β 1诱导的胰腺癌细胞耐药与PKC α表达有关。PKC α抑制剂Gö6976有望成为胰腺癌细胞化疗增敏剂。
Drug resistance remains a great challenge in the treatment of pancreatic cancer. The goal of this study was to determine whether TGF-β1 is associated with drug resistance in pancreatic cancer. Pancreatic cancer BxPC3 cells were stably transfected with TGF-β1 cDNA. Cellular morphology and cell cycle were determined and the suppressive subtracted hybridization (SSH) assay was performed to identify differentially expressed genes induced by TGF-β1. Western blotting and immunohistochemistry were used to detect expression of TGF-β1-related genes in the cells and tissue samples. After that, the cells were further treated with an anti-cancer drug (e.g., cisplatin) after pre-incubated with the recombinant TGF-β1 plus PKCα inhibitor Gö6976. TGF-β1 type II receptor, TβRII was also knocked down using TβRII siRNA to assess the effects of these drugs in the cells. Cell viability was assessed by MTT assay. Overexpression of TGF-β1 leads to a markedly increased invasion potential but a reduced growth rate in BxPC3 cells. Recombinant TGF-β1 protein increases expression of PKCα in BxPC3 cells, a result that we confirmed by SSH. Moreover, TGF-β1 reduced the sensitivity of BxPC3 cells to cisplatin treatment, and this was mediated by upregulation of PKCα. However, blockage of PKCα with Gö6976 and TβRII with siRNA reversed the resistance of BxPC3 cells to gemcitabine, even in the presence of TGF-β1. Immunohistochemical data show that pancreatic cancers overexpress TGF-β1 and P-gp relative to normal tissues. In addition, TGF-β1 expression is associated with P-gp and membranous PKCα expression in pancreatic cancer. TGF-β1-induced drug resistance in pancreatic cancer cells was associated with PKCα expression. The PKCα inhibitor Gö6976 could be a promising agent to sensitize pancreatic cancer cells to chemotherapy.
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