Siavash H, Nikitakis N G, Sauk J J
Department of Biomedical Sciences, University of Maryland, Baltimore, MD 21201, USA.
Br J Cancer. 2004 Sep 13;91(6):1074-80. doi: 10.1038/sj.bjc.6602055.
Cyclopentenone 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) exerts antineoplastic effects on various types of human cancer. We recently showed that treatment with 15d-PGJ(2) induces apoptosis accompanied by downregulation of the oncogenic signal transducer and activator of transcription 3 (Stat3) signalling in human oral squamous cell carcinoma (SCC) cells. The current study examines the effects of 15d-PGJ(2) on the epidermal growth factor receptor (EGFR) and Janus Kinase (JAK)-mediated signalling pathways. Inhibition of Stat3 by 15d-PGJ(2) was abolished by exogenous stimulation with transforming growth factor alpha (TGF-alpha), but not interleukin 6 (IL-6), supporting a selective effect of 15d-PGJ(2) on IL-6-mediated signalling. Importantly, 15d-PGJ(2) selectively abrogated constitutive and IL-6-mediated JAK phosphorylation without affecting EGFR-activated levels. Moreover, the inhibitory effect of 15d-PGJ(2) on JAK signalling required the reactive alpha,beta-unsaturated carbon within the cyclopentenone ring. Targeting of JAK signalling using a specific JAK inhibitor also abolished Stat3 phosphorylation and resulted in apoptosis in oral SCC cells. Our findings provide the first evidence for 15d-PGJ(2)-mediated downregulation of constitutive and IL-6-induced JAK signalling in cancer and support that JAK inhibition and suppression of EGFR-independent Stat3 activation by 15d-PGJ(2) represent a promising approach for induction of apoptosis in oral SCC cells.
环戊烯酮15-脱氧-Δ(12,14)-前列腺素J2（15d-PGJ2）对多种类型的人类癌症具有抗肿瘤作用。我们最近发现，用15d-PGJ2处理可诱导人口腔鳞状细胞癌（SCC）细胞凋亡，并伴随致癌信号转导和转录激活因子3（Stat3）信号通路的下调。本研究探讨了15d-PGJ2对表皮生长因子受体（EGFR）和Janus激酶（JAK）介导的信号通路的影响。用转化生长因子α（TGF-α）进行外源性刺激可消除15d-PGJ2对Stat3的抑制作用，但白细胞介素6（IL-6）不能，这支持了15d-PGJ2对IL-6介导信号通路的选择性作用。重要的是，15d-PGJ2选择性地消除了组成性和IL-6介导的JAK磷酸化，而不影响EGFR激活水平。此外，15d-PGJ2对JAK信号的抑制作用需要环戊烯酮环内的反应性α,β-不饱和碳。使用特异性JAK抑制剂靶向JAK信号也消除了Stat3磷酸化，并导致口腔SCC细胞凋亡。我们的研究结果首次证明了15d-PGJ2介导的癌症中组成性和IL-6诱导的JAK信号通路的下调，并支持15d-PGJ2抑制JAK和抑制EGFR非依赖性Stat3激活是诱导口腔SCC细胞凋亡的一种有前景的方法。
