Inhibition of TPL2 by interferon- suppresses bladder cancer through activation of PDE4D

doi:10.1186/s13046-018-0971-4

CORC > 成都生物研究所 > 中国科学院成都生物研究所 > 国家天然药物工程技术研究中心 > 天然产物研究

	Inhibition of TPL2 by interferon- suppresses bladder cancer through activation of PDE4D
	Qiang, Zhe 1,6; Zhou, Zong-yuan 1,6; Peng,Ting 1,6; Jiang, Pu-zi 5; Shi, Nan 1,6; Njoya,Emmanuel Mfotie 2,6; Azimova, Bahtigul 6; Liu, Wan-li 3; Chen, Wei-hua 4,5; Zhang, Guo-lin 6
刊名	JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
	2018
卷号	37 页码:288
关键词	Interferon TPL2 PDE4D cAMP COX-2
ISSN号	1756-9966
DOI	10.1186/s13046-018-0971-4
产权排序	1
文献子类	Article
英文摘要	BackgroundDrugs 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- (IFN-) is also used as a therapeutic agent for bladder cancer treatment but the response rate is low. It was found that IFN- 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- and MEK/ERK pathway will help enhance the efficacy of IFN- or MEK inhibitors on bladder cancer.MethodsImmunoprecipitation 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-2 (PGE(2)) 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.ResultsIFN- down-regulated the cyclooxygenase-2 (COX-2) expression in bladder cancer cells through the inhibition of TPL2/NF-B pathway; IFN- 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- 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.ConclusionsOur data reveal that IFN- 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- in the context of bladder cancer therapy. The antitumor effects of IFN- 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- and MEK inhibitors in bladder cancer treatment.
学科主题	Oncology
URL标识	查看原文
WOS关键词	MAP KINASE ; ALPHA SUPPRESSES ; PROSTATE-CANCER ; CROSS-TALK ; IN-VITRO ; CAMP ; INDUCTION ; PATHWAY ; PKA ; PHOSPHORYLATION
WOS研究方向	Oncology
语种	英语
出版者	BMC
WOS记录号	WOS:000451436500003
内容类型	期刊论文
源URL	[http://210.75.237.14/handle/351003/30626]
专题	国家天然药物工程技术研究中心_天然产物研究
作者单位	1.Univ Chinese Acad Sci, Beijing, Peoples R China 2.Univ Yaounde I, Dept Biochem, Fac Sci, Yaounde, Cameroon; 3.Tsinghua Univ, Sch Life Sci, Minist Educ, Key Lab Prot Sci, Beijing, Peoples R China; 4.Henan Normal Univ, Coll Life Sci, Xinxiang, Peoples R China; 5.Huazhong Univ Sci & Technol, Hubei Key Lab Bioinformat & Mol Imaging, Coll Life Sci & Technol, Key Lab Mol Biophys,Minist Educ,Dept Bioinformat, Wuhan, Hubei, Peoples R China; 6.Chinese Acad Sci, Chengdu Inst Biol, Key Lab Nat Med & Clin Translat, Chengdu, Sichuan, Peoples R China;
推荐引用方式 GB/T 7714	Qiang, Zhe,Zhou, Zong-yuan,Peng,Ting,et al. Inhibition of TPL2 by interferon- suppresses bladder cancer through activation of PDE4D[J]. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH,2018,37:288.
APA	Qiang, Zhe.,Zhou, Zong-yuan.,Peng,Ting.,Jiang, Pu-zi.,Shi, Nan.,...&Wang, Fei.(2018).Inhibition of TPL2 by interferon- suppresses bladder cancer through activation of PDE4D.JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH,37,288.
MLA	Qiang, Zhe,et al."Inhibition of TPL2 by interferon- suppresses bladder cancer through activation of PDE4D".JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH 37(2018):288.