Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, PR China.
Mol Cancer. 2009 Dec 21;8:125. doi: 10.1186/1476-4598-8-125.
One of the major reasons for poor prognosis of pancreatic cancer is its high resistance to currently available chemotherapeutic agents. In recent years, focal adhesion kinase (FAK), a central molecule in extracellular matrix (ECM)/integrin-mediated signaling, has been thought to be a key determinant of chemoresistance in cancer cells. In this study, we aimed to determine the roles of FAK phosphorylation in the intrinsic chemoresistance of pancreatic cancer cell lines.
Our results showed that, the level of constitutive phosphorylation of FAK at Tyr397 correlated with the extent of intrinsic resistance to Gemcitabine (Gem) in four pancreatic cancer cell lines. Moreover, in Panc-1 cells, which had high expression of pFAK, specific inhibition of constitutive FAK phosphorylation by either RNAi or FRNK overexpression decreased the phosphorylation of Akt, reduced the levels of survivin expression and Bad phosphorylation at Ser136 and increased Gem-induced cytotoxicity and apoptosis. However, in AsPC-1 cells with a low level of pFAK, neither FAK RNAi nor FRNK overexpression affected Gem-induced cell apoptosis. We further found that laminin (LN) induced FAK and Akt phosphorylation in a time-dependent manner, increased the levels of survivin and pBad (pS136) and decreased Gem-induced cytotoxicity and apoptosis in AsPC-1 cells; Specific inhibition of LN-induced FAK phosphorylation by either FAK RNAi or FRNK overexpression suppressed the effects of LN on AsPC-1 cells. Moreover, inhibition of constitutive FAK phosphorylation in Panc-1 cells and LN-induced FAK phosphorylation in AsPC-1 cells by a novel and more specific FAK phosphorylation inhibitor PF-573,228 showed similar results with those of FAK phosphorylation inhibition by FAK RNAi or FRNK overexpression.
In conclusion, our research demonstrates for the first time that both constitutive and LN-induced FAK phosphorylation contribute to increased intrinsic chemoresistance to Gem in pancreatic cancer cell lines and these effects are partly due to the regulation of Akt and Bad phosphorylation and survivin expression. Development of selective FAK phosphorylation inhibitors may be a promising way to enhance chemosensitivity in pancreatic cancer.
胰腺癌预后不良的主要原因之一是其对现有化疗药物的高度耐药性。近年来，粘着斑激酶（FAK）作为细胞外基质（ECM）/整合素介导的信号通路中的核心分子，被认为是癌细胞化疗耐药的关键决定因素。在这项研究中，我们旨在确定 FAK 磷酸化在胰腺癌细胞系固有化疗耐药中的作用。
我们的结果表明，在四个胰腺癌细胞系中，FAK 在 Tyr397 的组成性磷酸化水平与吉西他滨（Gem）的固有耐药程度相关。此外，在 Panc-1 细胞中，pFAK 表达水平较高，通过 RNAi 或 FRNK 过表达特异性抑制组成性 FAK 磷酸化可降低 Akt 的磷酸化，降低生存素表达水平和 Bad 在 Ser136 的磷酸化，并增加 Gem 诱导的细胞毒性和细胞凋亡。然而，在 pFAK 水平较低的 AsPC-1 细胞中，FAK RNAi 或 FRNK 过表达均不影响 Gem 诱导的细胞凋亡。我们进一步发现，层粘连蛋白（LN）可时间依赖性地诱导 FAK 和 Akt 磷酸化，增加生存素和 pBad（pS136）的水平，并降低 AsPC-1 细胞中 Gem 诱导的细胞毒性和细胞凋亡；通过 FAK RNAi 或 FRNK 过表达特异性抑制 LN 诱导的 FAK 磷酸化可抑制 LN 对 AsPC-1 细胞的作用。此外，新型且更特异的 FAK 磷酸化抑制剂 PF-573,228 抑制 Panc-1 细胞中组成性 FAK 磷酸化和 AsPC-1 细胞中 LN 诱导的 FAK 磷酸化的效果与 FAK RNAi 或 FRNK 过表达抑制 FAK 磷酸化的效果相似。
总之，我们的研究首次表明，组成性和 LN 诱导的 FAK 磷酸化均有助于增加胰腺癌细胞系对 Gem 的内在化疗耐药性，这些作用部分归因于 Akt 和 Bad 磷酸化和生存素表达的调节。开发选择性的 FAK 磷酸化抑制剂可能是增强胰腺癌化疗敏感性的一种有前途的方法。
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