Lee Jun Hee, Yun Chul Won, Lee Sang Hun
Department of Pharmacology and Toxicology, University of Alabama at Birmingham School of Medicine, Birmingham, AL 35294, USA.
Medical Science Research Institute, Soonchunhyang University Seoul Hospital, Seoul 04401, Republic of Korea.
Biomol Ther (Seoul). 2018 May 1;26(3):313-321. doi: 10.4062/biomolther.2017.033.
Anti-cancer drug resistance is a major problem in colorectal cancer (CRC) research. Although several studies have revealed the mechanism of cancer drug resistance, molecular targets for chemotherapeutic combinations remain elusive. To address this issue, we focused on the expression of cellular prion protein (PrP) in 5-FU-resistant CRC cells. In 5-FU-resistant CRC cells, PrP expression is significantly increased, compared with that in normal CRC cells. In the presence of 5-FU, PrP increased CRC cell survival and proliferation by maintaining the activation of the PI3K-Akt signaling pathway and the expression of cell cycle-associated proteins, including cyclin E, CDK2, cyclin D1, and CDK4. In addition, PrP inhibited the activation of the stress-associated proteins p38, JNK, and p53. Moreover, after treatment of 5-FU-resistant CRC cells with 5-FU, silencing of PrP triggered apoptosis via the activation of caspase-3. These results indicate that PrP plays a key role in CRC drug resistance. The novel strategy of combining chemotherapy with PrP targeting may yield efficacious treatments of colorectal cancer.
抗癌药物耐药性是结直肠癌（CRC）研究中的一个主要问题。尽管多项研究揭示了癌症耐药性的机制，但化疗联合方案的分子靶点仍不明确。为了解决这个问题，我们聚焦于细胞朊蛋白（PrP）在5-氟尿嘧啶（5-FU）耐药性CRC细胞中的表达。与正常CRC细胞相比，在5-FU耐药性CRC细胞中，PrP表达显著增加。在5-FU存在的情况下，PrP通过维持PI3K-Akt信号通路的激活以及细胞周期相关蛋白（包括细胞周期蛋白E、细胞周期蛋白依赖性激酶2（CDK2）、细胞周期蛋白D1和CDK4）的表达，增加了CRC细胞的存活和增殖。此外，PrP抑制了应激相关蛋白p38、JNK和p53的激活。而且，在用5-FU处理5-FU耐药性CRC细胞后，PrP的沉默通过激活caspase-3触发了细胞凋亡。这些结果表明，PrP在CRC耐药性中起关键作用。将化疗与靶向PrP相结合的新策略可能会产生有效的结直肠癌治疗方法。
