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

Zhang,Xing; Lu,Hong; Hong,Weilong; Liu,Leping; Wang,Silu; Zhou,Mengtao; Chen,Bicheng; Bai,Yongheng

doi:10.3892/or.2018.6241

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

Authors:
- Xing Zhang
- Hong Lu
- Weilong Hong
- Leping Liu
- Silu Wang
- Mengtao Zhou
- Bicheng Chen
- Yongheng Bai
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Affiliations: Key Laboratory of Diagnosis and Treatment of Severe Hepato‑Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China, Department of Laboratory Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
Published online on: January 31, 2018 https://doi.org/10.3892/or.2018.6241
Pages: 1892-1900

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Abstract

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‑1α, 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.

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