METHODS: Pancreatic cancer cell lines were treated with or without DUV. TLK1 expression and phosphorylation in the two groups were examined. Then, these cancer cell lines were treated with thioridazine (THD), DUV or both. Thereafter, cytomorphology and apoptosis were assessed. Several proteins related to DNA damage, were analyzed in cancer cells treated with DUV and THD. Tumors in a subcutaneous xenograft model were treated with THD, DUV, or both for six weeks.
RESULTS: DUV irradiation induced the phosphorylation of TLK1 in pancreatic cancer cell lines. Cytomorphology was significantly changed in pancreatic cancer cells treated with DUV and THD. TLK1 inhibition enhanced DUV irradiation-induced apoptosis in cancer cells. Interestingly, CHK1 and pCHK1 expression was suppressed after TLK1 inhibition. In addition, inhibition of MRE11 led to a decrease in the expression of CHK1 and pCHK1, accompanied by a notable increase in apoptosis. In the subcutaneous xenograft models, the tumor volume in the DUV and THD groups was lower than that in the other groups.
CONCLUSIONS: TLK1 phosphorylation is an important event in DUV irradiation. DUV irradiation combined with TLK1 inhibition has therapeutic potential in pancreatic cancer cells.
方法:用或不用DUV处理胰腺癌细胞系。检测两组TLK1表达及磷酸化情况。然后,这些癌细胞系用硫利达嗪(THD)处理,DUV或两者。此后,细胞形态学和细胞凋亡进行了评估。与DNA损伤相关的几种蛋白质,在用DUV和THD处理的癌细胞中进行分析。用THD治疗皮下异种移植模型中的肿瘤,DUV,或者两者都持续六周。
结果:DUV照射诱导胰腺癌细胞系TLK1磷酸化。在用DUV和THD处理的胰腺癌细胞中,细胞形态学显著改变。TLK1抑制增强DUV照射诱导的癌细胞凋亡。有趣的是,TLK1抑制后,CHK1和pCHK1的表达受到抑制。此外,MRE11的抑制导致CHK1和pCHK1的表达减少,并伴有细胞凋亡的显着增加。在皮下异种移植模型中,DUV和THD组的肿瘤体积低于其他组。
结论:TLK1磷酸化是DUV照射中的重要事件。DUV照射联合TLK1抑制在胰腺癌细胞中具有治疗潜力。