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胰腺癌细胞系中对吉西他滨的内在化疗耐药与组成性和层黏连蛋白诱导的FAK磷酸化相关 |
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Intrinsic chemoresistance to gemcitabine is associated with constitutive and laminin-induced phosphorylation of FAK in pancreatic cancer cell lines |
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Huanwen W, Zhiyong L, Xiaohua S, Xinyu R, Kai W, Tonghua L 2010/2/10 15:19:00 |
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Molecular Cancer, 2009, Volume 8,
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Background: 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.Results: 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.Conclusions: 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. © 2009 Huanwen et al; licensee BioMed Central Ltd.
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Correspondence Address: Tonghua, L.; Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing 100730, China; email:liuth_pumch@yahoo.com.cn |
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疾病资源中心
王燕燕 王曙
上海交通大学附属瑞金医院内分泌科
患者,女,69岁。2009年1月无明显诱因下出现乏力,当时程度较轻,未予以重视。2009年3月患者乏力症状加重,尿色逐渐加深,大便习惯改变,颜色变淡。4月18日入我院感染科治疗,诉轻度头晕、心慌,体重减轻10kg。无肝区疼痛,无发热,无腹痛、腹泻、腹胀、里急后重,无恶性、呕吐等。入院半月前于外院就诊,查肝功能:ALT 601IU/L,AST 785IU/L,TBIL 97.7umol/L,白蛋白 41g/L,甲状腺功能:游离T3 30.6pmol/L,游离T4 51.9pmol/L,心电图示快速房颤。
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