Abstract
BackgroundOne 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.ResultsOur 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.ConclusionsIn 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.
Highlights
One of the major reasons for poor prognosis of pancreatic cancer is its high resistance to currently available chemotherapeutic agents
The level of constitutive phosphorylation of focal adhesion kinase (FAK) at Tyr397 correlates with the extent of intrinsic chemoresistance to Gem in pancreatic cancer cell lines Western blot was used to determine constitutive FAK and pFAK expression in four pancreatic cancer cell
Comparable protein levels of total FAK were found in these cell lines, whereas different levels of constitutive FAK phosphorylation were detected in these cell lines
Summary
One of the major reasons for poor prognosis of pancreatic cancer is its high resistance to currently available chemotherapeutic agents. Due to high intrinsic resistance of pancreatic cancer to currently available agents, clinical trials have shown that Gem alone and Gem-based combination chemotherapy are not likely to achieve great success [3,4,6]. Tyrosine kinases have demonstrated great promise as therapeutic targets for cancers, and combinations of appropriate tyrosine kinase inhibitors (TKIs) with cytotoxic agents such as Gem have been demonstrated to improve the prognosis of pancreatic cancer [7,10,11]. The modulation of FAK expression and (or) phosphorylation influences the sensitivity of tumor cells to various chemotherapeutic agents, and combination of the selective FAK inhibitors with cytotoxic agents might be a very promising anti-cancer therapy [14,15,16]. We first investigated the correlation between the level of constitutive FAK expression and phosphorylation and the extent of chemoresistance in four pancreatic cancer cell lines
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