Lee Jong Hyun, Kim Chulwon, Baek Seung Ho, Ko Jeong-Hyeon, Lee Seok Geun, Yang Woong Mo, Um Jae-Young, Sethi Gautam, Ahn Kwang Seok
College of Korean Medicine, Kyung Hee University, Seoul 130-701, Republic of Korea.
Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597.
Oncotarget. 2017 Mar 14;8(11):17700-17711. doi: 10.18632/oncotarget.10775.
Persistent STAT3 activation is seen in many tumor cells and promotes malignant transformation. Here, we investigated whether capsazepine (Capz), a synthetic analogue of capsaicin, exerts anticancer effects by inhibiting STAT3 activation in prostate cancer cells. Capz inhibited both constitutive and induced STAT3 activation in human prostate carcinoma cells. Capz also inhibited activation of the upstream kinases JAK1/2 and c-Src. The phosphatase inhibitor pervanadate reversed Capz-induced STAT3 inhibition, indicating that the effect of Capz depends on a protein tyrosine phosphatase. Capz treatment increased PTPε protein and mRNA levels. Moreover, siRNA-mediated knockdown of PTPε reversed the Capz-induced induction of PTPε and inhibition of STAT3 activation, indicating that PTPε is crucial for Capz-dependent STAT3 dephosphorylation. Capz also decreased levels of the protein products of various oncogenes, which in turn inhibited proliferation and invasion and induced apoptosis. Finally, intraperitoneal Capz administration decreased tumor growth in a xenograft mouse prostate cancer model and reduced p-STAT3 and Ki-67 expression. These data suggest that Capz is a novel pharmacological inhibitor of STAT3 activation with several anticancer effects in prostate cancer cells.
在许多肿瘤细胞中都可见到持续的信号转导和转录激活因子3（STAT3）激活，其可促进恶性转化。在此，我们研究了辣椒素的合成类似物辣椒平（Capz）是否通过抑制前列腺癌细胞中的STAT3激活发挥抗癌作用。Capz抑制人前列腺癌细胞中组成型和诱导型STAT3激活。Capz还抑制上游激酶JAK1/2和c-Src的激活。磷酸酶抑制剂过钒酸钠可逆转Capz诱导的STAT3抑制，表明Capz的作用依赖于蛋白酪氨酸磷酸酶。Capz处理可增加PTPε蛋白和mRNA水平。此外，小干扰RNA（siRNA）介导的PTPε敲低可逆转Capz诱导的PTPε诱导和STAT3激活抑制，表明PTPε对Capz依赖的STAT3去磷酸化至关重要。Capz还降低了各种癌基因蛋白产物的水平，进而抑制增殖和侵袭并诱导凋亡。最后，在异种移植小鼠前列腺癌模型中腹腔注射Capz可减少肿瘤生长，并降低磷酸化STAT3和Ki-67的表达。这些数据表明，Capz是一种新型的STAT3激活药理学抑制剂，在前列腺癌细胞中具有多种抗癌作用。
