Key Laboratory of Natural Medicine and Clinical Translation, Chengdu Institute of Biology, Chinese Academy of Science, Chengdu, China.
University of Chinese Academy of Sciences, Beijing, China.
J Exp Clin Cancer Res. 2018 Nov 27;37(1):288. doi: 10.1186/s13046-018-0971-4.
Drugs that inhibit the MEK/ERK pathway have therapeutic benefit in bladder cancer treatment but responses vary with patients, for reasons that are still not very clear. Interferon-α (IFN-α) is also used as a therapeutic agent for bladder cancer treatment but the response rate is low. It was found that IFN-α could enhance the cytotoxic effect of MEK inhibition. However, the potential mechanisms of that are still unclear. Understanding of the cross-talk between the IFN-α and MEK/ERK pathway will help enhance the efficacy of IFN-α or MEK inhibitors on bladder cancer.
Immunoprecipitation and pull-down assay were used to reveal the formation of signaling complex. The protein expressions were detected by western blot and immunohistochemistry. The cAMP level, Phosphodiesterase 4D (PDE4D) activity and Prostaglandin E (PGE) concentration in cells, serum and tissues were detected by enzyme-linked immunosorbent assay. The role of PDE4D in bladder tumorigenesis in vivo was examined by the xenograft model. Tissue microarray chips were used to investigate the prognostic roles of PDE4D and tumor progression locus 2 (TPL2) in bladder cancer patients.
IFN-α down-regulated the cyclooxygenase-2 (COX-2) expression in bladder cancer cells through the inhibition of TPL2/NF-κB pathway; IFN-α also inhibited COX-2 expression by suppressing cAMP signaling through TPL2-ERK mediated PDE4D activity. Reduction of the intracellular cAMP level by PDE4D potentiated the antitumor effect of IFN-α against bladder cancer in vitro and in vivo. Further analysis of clinical samples indicated that low PDE4D expression and high level of TPL2 phosphorylation were correlated to the development and poor prognosis in bladder cancer patients.
Our data reveal that IFN-α can exert its antitumor effect through a non-canonical JAK-STAT pathway in the bladder cancer cells with low activity of IFN pathway, and the TPL2 inhibition is another function of IFN-α in the context of bladder cancer therapy. The antitumor effects of IFN-α and MEK inhibition also depend on the PDE4D-mediated cAMP level in bladder cancer cells. Suppression of the TPL2 phosphorylation and intracellular cAMP level may be possible therapeutic strategies for enhancing the effectiveness of IFN-α and MEK inhibitors in bladder cancer treatment.
抑制 MEK/ERK 通路的药物在膀胱癌治疗中有治疗益处，但由于原因尚不清楚，患者的反应各不相同。干扰素-α（IFN-α）也被用作膀胱癌治疗的治疗剂，但反应率较低。研究发现，IFN-α 可以增强 MEK 抑制的细胞毒性作用。然而，其潜在机制尚不清楚。了解 IFN-α 和 MEK/ERK 通路之间的串扰将有助于提高 IFN-α 或 MEK 抑制剂对膀胱癌的疗效。
免疫沉淀和下拉测定用于揭示信号复合物的形成。通过 Western blot 和免疫组织化学检测蛋白表达。通过酶联免疫吸附试验检测细胞、血清和组织中的 cAMP 水平、磷酸二酯酶 4D（PDE4D）活性和前列腺素 E（PGE）浓度。通过异种移植模型检查 PDE4D 在体内膀胱癌发生中的作用。组织微阵列芯片用于研究 PDE4D 和肿瘤进展位点 2（TPL2）在膀胱癌患者中的预后作用。
IFN-α 通过抑制 TPL2/NF-κB 通路下调膀胱癌细胞中环氧化酶-2（COX-2）的表达；IFN-α 还通过 TPL2-ERK 介导的 PDE4D 活性抑制 cAMP 信号来抑制 COX-2 表达。通过 PDE4D 降低细胞内 cAMP 水平增强了 IFN-α 对体外和体内膀胱癌的抗肿瘤作用。对临床样本的进一步分析表明，低 PDE4D 表达和高 TPL2 磷酸化水平与膀胱癌患者的发展和预后不良相关。
我们的数据表明，IFN-α 可以通过低 IFN 通路活性的膀胱癌细胞中的非典型 JAK-STAT 途径发挥其抗肿瘤作用，TPL2 抑制是 IFN-α 在膀胱癌治疗中的另一种作用。IFN-α 和 MEK 抑制的抗肿瘤作用也取决于膀胱癌细胞中 PDE4D 介导的 cAMP 水平。抑制 TPL2 磷酸化和细胞内 cAMP 水平可能是增强 IFN-α 和 MEK 抑制剂在膀胱癌治疗中的有效性的可能治疗策略。
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