Signal transducers and activators of transcription (STAT) were originally identified as components of cytokine signal transduction pathways but are now also recognized as key regulators of apoptosis, proliferation, angiogenesis and immune responses in many malignant diseases. Activation of STAT3 occurs by the binding of various cytokines to its receptors leading to the activation of the JAK/ STAT3 signaling pathway. Of these cytokines, interleukin-6 (IL-6) has been implicated in regulating growth of various malignant tumors. Activated IL-6 has also been shown to be elevated in the sera from patients with metastatic prostate cancer, and persistent activation of STAT3 is a common feature. To better characterize the potential role of JAK/STAT3 as a therapeutic target for advanced prostate cancer, we used the JAK1/2 inhibitor, AZD1480 to suppress the transcriptional activation of STAT3 in a PTEN-conditional knockout mouse model of prostate cancer. Prostate tumors from homozygous PTEN-mutant mice share many characteristics of human prostate cancer, including increased activation of the JAK/STAT3 signaling cascade. Our pharmacodynamic studies show that AZD1480 elicited a strong inhibition of STAT3 signal activation leading to decreased tumor cell proliferation, and induction of apoptosis. Our drug intervention studies show that persistent suppression of STAT3 signaling results in a reduction of tumor growth characterized by a decrease in tumor cell proliferation, induction of apoptosis, and decreased angiogenesis. However, PI3K/Akt and MAPK signaling were upregulated in response to STAT3 signal inhibition. Our findings show a strong antitumor effect for STAT3 signal inhibition and may be a promising therapeutic option for prostate cancer; however, it still requires further optimization in order to maximize its clinical potential.

Citation Format: Marco A. De Velasco, Yurie Kura, Naomi Ando, Emiko Fukushima, Yuji Hatanaka, Yutaka Yamamoto, Nobutaka Shimizu, Masahiro Nozawa, Kazuhiro Yoshimura, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura. Therapeutic potential of JAK/STAT signal inhibition in prostate cancer by the JAK inhibitor AZD1480. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 906. doi:10.1158/1538-7445.AM2013-906

©2013 American Association for Cancer Research
2013