2-NP is a cell-penetrating, selective signal transduction and transcription activator 1 (STAT1) transcription enhancer[1]. 2-NP enhances IFN‑γ‑induced STAT1 phosphorylation and the expression of its target genes (such as IRF3 and IRF1) without affecting the STAT3 or NF‑κB pathways. 2-NP is commonly used in research areas such as STAT1‑dependent antitumor immunity (such as breast cancer, fibrosarcoma, and non‑small cell lung cancer) and IFN‑γ signal amplification[2,3,4].
In vitro, pretreatment of human non‑small cell lung cancer A549 cells with 2-NP (0.072-45μM) for 1h followed by stimulation with IL‑27 (50ng/mL) enhanced STAT1 phosphorylation while reducing STAT3 phosphorylation levels, resulting in a significant increase in the STAT1/STAT3 activation ratio compared with IL‑27 treatment alone[5]. Treatment of follistatin‑like 1 (FSTL1)-silenced mesenchymal stem cells (MSCs) with 2-NP (15μg/mL) for 12h (for mRNA) or 24h (for protein) significantly upregulated the mRNA and protein expression levels of indoleamine 2,3‑dioxygenase (IDO)[6].
In vivo, rats were given 2-NP (15μg/kg) via intracerebroventricular (i.c.v.) injection 48h before subarachnoid hemorrhage (SAH) induction, followed by intranasal administration of PEDF‑34 (3μg/kg) 1h after SAH. At 24h post‑SAH, 2-NP significantly reversed the PEDF‑34‑induced downregulation of the pro‑inflammatory cytokines TNF‑α and IL‑1β, as well as the upregulation of the anti‑inflammatory cytokine IL‑10[7].
References:
[1] Lynch R A, Etchin J, Battle T E, et al. A small-molecule enhancer of signal transducer and activator of transcription 1 transcriptional activity accentuates the antiproliferative effects of IFN-γ in human cancer cells[J]. Cancer research, 2007, 67(3): 1254-1261.
[2] Wang W, Lopez McDonald M C, Hariprasad R, et al. Oncogenic STAT transcription factors as targets for cancer therapy: innovative strategies and clinical translation[J]. Cancers, 2024, 16(7): 1387.
[3] Kachroo P, Lee M, Lee G, et al. IL-27 Mediated Inhibition of Epithelial to Mesenchymal Transition is Augmented by STAT1 Activator, 2-(1, 8-naphthyridin-2-yl) phenol (2-NP) in Human Non-small Cell Lung Cancer[J]. Journal of Surgical Research, 2012, 172(2): 243.
[4] Mahmood N, Arakelian A, Muller W J, et al. An enhanced chemopreventive effect of methyl donor S-adenosylmethionine in combination with 25-hydroxyvitamin D in blocking m
[5] Weber C E, Talbot L J, Wai P Y, et al. Transformation of mesenchymal stem cells into cancer associated fibroblasts within the tumor microenvironment[J]. Journal of Surgical Research, 2012, 172(2): 243.
[6] Zheng X, Zhou X, Ma G, et al. Endogenous Follistatin-like 1 guarantees the immunomodulatory properties of mesenchymal stem cells during liver fibrotic therapy[J]. Stem Cell Research & Therapy, 2022, 13(1): 403.
[7] Wu L, Liu Y, He Q, et al. PEDF-34 attenuates neurological deficit and suppresses astrocyte-dependent neuroinflammation by modulating astrocyte polarization via 67LR/JNK/STAT1 signaling pathway after subarachnoid hemorrhage in rats[J]. Journal of neuroinflammation, 2024, 21(1): 178.