順鉑在人類膀胱癌細胞中透過ERK/AP-1信息傳遞
誘發細胞程式死亡-配體1 (PD-L1)表現
黃一勝1,2,3,4、蔡德甫1、陳栢均5、楊尚哲5、陳宏恩1、林宜佳1,4、仇光宇1、林致凡5
1新光醫院 外科部、2新光醫院 泌尿科、3台北醫學大學 醫學院、4輔仁大學 醫學院、
5新光醫院 中央研究室
Cis-platinum induce PD-L1 expression through ERK/AP-1 signal cascade in bladder cancer cells
Thomas I-Sheng Hwang1,2,3,4, Po-Chun Chen5, Te-Fu Tsai 1, Shan-Che Yang5, Hung-En Chen1, Yi-Chia Lin1,4, Kuang-Yu Chou1, and Ji-Fan Lin5
Department of Surgery, Shin Kong Wu Ho-Su Memorial Hospital1, Department of Urology, Shin Kong Wu Ho-Su Memorial Hospital2, Department of Urology, Taipei Medical University3, Division of Urology, School of Medicine, Fu-Jen Catholic University4, Central Laboratory, Shin Kong Wu Ho-Su Memorial Hospital5, Taipei, Taiwan.
Background
Cis-platinum has been used as a main therapeutic agent in advanced or metastatic bladder cancer (BC). The immune checkpoint protein, programmed death-ligand 1 (PD-L1) is one of the main targets for immunotherapy. It has been demonstrated that PD-L1 is overexpressed according to the bladder cancer progression. In this study, PD-L1 expression status after cis-platinum treatment was investaigated.
Materials and methods
T24 and 5637 BC cells were treated with various concentrations of cis-platinum (0, 6.25, 12.5, and 25 μM) for 24 h. The Western blot and quantitative real-time PCR (qPCR) were used to define the expression level of PD-L1 after cis-platinum treatment in bladder cancer cells. Western blot was performed in T24 and 5637 BC cells treated with the same conditions to evaluate the signal transduction that regulates PD-L1 expression. Finally, immunofluorescence by anti-c-Jun antibody was performed in T24 and 5637 BC cells treated with cis-platinum to examine the nuclear translocation of AP-1 transcription factor.
Results:
We found that chemotherapeutic drug cisplatin can induce PD-L1 but not PD-L2 expression in BC cells. Furthermore, the expression level of PD-L1 was increased in a dose- and time- dependent manner after cisplatin treatment. The cisplatin-induced PD-L1 expression is mainly mediated by ERK but not Akt/mTOR signal pathway. Moreover, we found that cisplatin activates transcription factor AP-1 to regulate PD-L1 expression.
Conclusion:
The chemotherapy drug such as cis-platinum may trigger resistance of bladder cancer through PD-L1 up-regulation. This study suggests that PD-L1 antibody should be used concomitantly with chemotherapy in the setting of advanced and metastatic BC.
Keywords: cisplatin, PD-L1, ERK, AP-1, Bladder cancer cells.