Tyrphostin B42 attenuates trichostatin A-mediated resistance in pancreatic cancer cells by antagonizing IL-6/JAK2/STAT3 signaling

被引:17
|
作者
Zhang, Xing [1 ]
Lu, Hong [2 ]
Hong, Weilong [1 ]
Liu, Leping [1 ]
Wang, Silu [1 ]
Zhou, Mengtao [1 ,3 ]
Chen, Bicheng [1 ]
Bai, Yongheng [1 ]
机构
[1] Wenzhou Med Univ, Affiliated Hosp 1, Key Lab Diag & Treatment Severe Hepatopancreat D, 2 Fuxue Lane, Wenzhou 325000, Zhejiang, Peoples R China
[2] Wenzhou Med Univ, Affiliated Hosp 1, Dept Lab Med, Wenzhou 325000, Zhejiang, Peoples R China
[3] Wenzhou Med Univ, Affiliated Hosp 1, Dept Hepatobiliary Surg, Wenzhou 325000, Zhejiang, Peoples R China
基金
中国国家自然科学基金;
关键词
tyrphostin B42 (AG490); pancreatic cancer; trichostatin A; chemotherapy resistance; IL-6/JAK2/STAT3; signaling; EPITHELIAL-MESENCHYMAL TRANSITION; HISTONE DEACETYLASE; JAK/STAT PATHWAY; GENE-EXPRESSION; INHIBITION; APOPTOSIS; GEMCITABINE; STAT3; CARCINOMA; LINES;
D O I
10.3892/or.2018.6241
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Drug-resistance is the key reason for the ineffectiveness of chemotherapy in pancreatic cancer. Thus, it is very important to explore the molecular mechanisms of drug-resistance and the methods of effective intervention. In the present study, we investigated the effect of tyrphostin B42, also called AG490, on histone deacetylase (HDAC) inhibitor trichostatin A (TSA)-induced resistance in pancreatic cancer cells (PCCs). Evidence from phase contrast microscope revealed that TSA-resistant cells (PANC-1-TSA) had higher proliferative activity than non-resistant cells (PANC-1). This over-proliferative activity induced by TSA may be associated with abnormal activation of JAK2/STAT3 signaling, which can be strengthened by interleukin-6 (IL-6), a STAT3-upstream inducer, resulting in enhanced expression of STAT3-downstream target genes including c-Myc, c-Src, HIF-1 alpha, and CCND1. In addition, increased expression of Bcl-2 mRNA and decreased expression of Bax mRNA in PANC-1-TSA cells indicated that TSA induced the inhibition of mitochondrial-dependent apoptosis in PCCs. Tyrphostin B42 treatment evidently antagonized the activation of IL-6/JAK2/STAT3 in a dose-dependent manner. As a result, tyrphostin B42 inhibited the over-proliferative activity of PANC-1-TSA cells, and downregulated the expression of IL-6/JAK2/STAT3-downstream target genes. Moreover, tyrphostin B42 induced the apoptosis of PCCs by regulating the expression of mitochondrial-related genes. Therefore, these findings demonstrated that tyrphostin B42 attenuated TSA-mediated resistance in PCCs by antagonizing the IL-6/JAK2/STAT3 signaling.
引用
收藏
页码:1892 / 1900
页数:9
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