Mhaidat Nizar M, Alzoubi Karem H, Khabour Omar F, Banihani Mohammed N, Al-Balas Qosay A, Swaidan Sulaiman
Department of Clinical Pharmacy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, 22110, Jordan.
Faculty of Applied Medical Sciences, Jordan University of Science and Technology, Irbid, Jordan.
Cytotechnology. 2016 May;68(3):459-67. doi: 10.1007/s10616-014-9799-8. Epub 2014 Nov 16.
This study was carried out to investigate the activation status of unfolded protein response (UPR) in colorectal cancer (CRC) and its contribution to CRC resistance to chemotherapy-induced apoptosis. Chemotherapy-induced apoptosis was assessed by the propidium iodide method. Activation of UPR was evaluated in CRC cell lines using immunoblotting technique and in CRC tissues using immunohistochemistry. Findings of the present study revealed that the UPR is constitutively activated in CRC cell lines and CRC tissues isolated from patients, as evidenced by relatively high levels of the 78-kDa glucose-regulated protein (GRP78) and spliced X-box-binding protein 1 mRNA in tissue samples. In addition, CRC cell lines differentially responded to clinically relevant DNA-targeting agents including cisplatin, and 5-flourouracil. Moreover, the levels of GRP78 were inversely associated with sensitivity of CRC cells to chemotherapy-induced apoptosis. Inhibition of GRP78 by siRNA resulted in increased sensitivity of CRC cells to chemotherapeutic agents. Collectively, current results appear to provide novel insights into the role of UPR in determining sensitivity of CRC cells to chemotherapeutic agents and might have important implications for personalized CRC treatment.
本研究旨在探讨结直肠癌（CRC）中未折叠蛋白反应（UPR）的激活状态及其对CRC化疗诱导凋亡抗性的影响。采用碘化丙啶法评估化疗诱导的凋亡。使用免疫印迹技术在CRC细胞系中评估UPR的激活情况，并使用免疫组织化学方法在CRC组织中进行评估。本研究结果显示，从患者分离的CRC细胞系和CRC组织中，UPR呈组成性激活，组织样本中78 kDa葡萄糖调节蛋白（GRP78）和剪接的X盒结合蛋白1 mRNA水平相对较高即证明了这一点。此外，CRC细胞系对包括顺铂和5-氟尿嘧啶在内的临床相关DNA靶向药物有不同反应。而且，GRP78水平与CRC细胞对化疗诱导凋亡的敏感性呈负相关。通过小干扰RNA抑制GRP78可导致CRC细胞对化疗药物的敏感性增加。总体而言，目前的结果似乎为UPR在决定CRC细胞对化疗药物敏感性中的作用提供了新的见解，可能对CRC个性化治疗具有重要意义。
