Wang Hui, Cai Jun, Du Shaoxia, Guo Zhongkui, Xin Beibei, Wang Juan, Wei Wei, Shen Xiaohong
School of Medicine, Nankai University, Tianjin, China.
National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
Cell Biochem Funct. 2017 Aug;35(6):315-326. doi: 10.1002/cbf.3278.
Fractalkine (FKN, CX3CL1) is highly expressed in a majority of malignant solid tumours. Fractalkine is the only known ligand for CX3CR1. In this study, we performed an analysis to determine the effects of fractalkine/CX3CR1 on modulating apoptosis and explored the related mechanisms. The expression of fractalkine/CX3CR1 was detected by immunohistochemistry and western blotting. The levels of AKT/p-AKT, BCL-xl, and BCL-2 were detected by western blotting. Then, the effects of exogenous and endogenous fractalkine on the regulation of tumour apoptosis and proliferation were investigated. The mechanism of fractalkine/CX3CR1 on modulating apoptosis in cancer cells through the activation of AKT/NF-κB/p65 signals was evaluated. The effect of fractalkine on regulating cell cycle distribution was also tested. Fractalkine, AKT/p-AKT, and apoptotic regulatory proteins BCL-xl and BCL-2 were highly expressed in human pancreatic cancer tissues. In vitro, fractalkine/CX3CR1 promoted proliferation and mediated resistance to apoptosis in pancreatic cancer cells. The antiapoptotic effect of fractalkine was induced by the activation of AKT/NF-κB/p65 signalling in pancreatic cancer cells. The NF-κB/p65 contributes to promote the expressions of BCL-xl and BCL-2 and reduce caspase activity, thereby inhibiting apoptotic processes. Treatment with fractalkine resulted in the enrichment of pancreatic cancer cells in S phase with a concomitant decrease in the number of cells in G1 phase. The present study demonstrated the function of fractalkine in the activation of the AKT/NF-κB/p65 signalling cascade and mediation of apoptosis resistance in pancreatic cancer cells. Fractalkine/CX3CR1 could serve as a diagnostic marker and as a potential target for chemotherapy in early stage pancreatic cancer. Pancreatic cancer is characterized by local recurrence, neural invasion, or distant metastasis. The present study demonstrated the overexpression of fractalkine/CX3CR1 in pancreatic cancer tissues, indicating its important role in the tumourigenesis of pancreatic cancer, and suggested that the overexpression of fractalkine/CX3CR1 could serve as a diagnostic marker for pancreatic cancer. Moreover, we reveal the mechanism that fractalkine functions on the activation of the AKT/NF-κB/p65 signalling cascade and regulation of the antiapoptosis process in pancreatic cancer cells. Fractalkine/CX3CR1 could serve as an effective therapeutic target of chemotherapeutic and biologic agents in early stage pancreatic cancer.
趋化因子（FKN，CX3CL1）在大多数恶性实体瘤中高表达。趋化因子是已知的CX3CR1唯一配体。在本研究中，我们进行了一项分析以确定趋化因子/CX3CR1对调节细胞凋亡的影响，并探索相关机制。通过免疫组织化学和蛋白质印迹法检测趋化因子/CX3CR1的表达。通过蛋白质印迹法检测AKT/p-AKT、BCL-xl和BCL-2的水平。然后，研究外源性和内源性趋化因子对肿瘤细胞凋亡和增殖调节的影响。评估趋化因子/CX3CR1通过激活AKT/NF-κB/p65信号通路调节癌细胞凋亡的机制。还测试了趋化因子对调节细胞周期分布的影响。趋化因子、AKT/p-AKT以及凋亡调节蛋白BCL-xl和BCL-2在人胰腺癌组织中高表达。在体外，趋化因子/CX3CR1促进胰腺癌细胞增殖并介导其对凋亡的抵抗。趋化因子的抗凋亡作用是由胰腺癌细胞中AKT/NF-κB/p65信号通路的激活诱导的。NF-κB/p65有助于促进BCL-xl和BCL-2的表达并降低半胱天冬酶活性，从而抑制凋亡过程。用趋化因子处理导致胰腺癌细胞在S期富集，同时G1期细胞数量减少。本研究证明了趋化因子在激活AKT/NF-κB/p65信号级联反应以及介导胰腺癌细胞抗凋亡中的作用。趋化因子/CX3CR1可作为早期胰腺癌的诊断标志物和潜在化疗靶点。胰腺癌的特征是局部复发、神经侵犯或远处转移。本研究证明趋化因子/CX3CR1在胰腺癌组织中过表达，表明其在胰腺癌发生中的重要作用，并提示趋化因子/CX3CR1的过表达可作为胰腺癌的诊断标志物。此外，我们揭示了趋化因子在激活AKT/NF-κB/p65信号级联反应以及调节胰腺癌细胞抗凋亡过程中的作用机制。趋化因子/CX3CR1可作为早期胰腺癌化疗和生物制剂的有效治疗靶点。
