AG490, a Jak2 inhibitor, suppressed the progression of murine ovarian cancer.
AG490, a Jak2 inhibitor, suppressed the progression of murine ovarian cancer.
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DOI：
10.1016/j.ejphar.2015.09.039
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发表时间：
2015-11
影响因子：
5
通讯作者：
A. Kobayashi;Yuko Tanizaki;A. Kimura;Y. Ishida;M. Nosaka;S. Toujima;Y. Kuninaka;Sawako Minami;K. Ino;T. Kondo
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文献类型：
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作者：
A. Kobayashi;Yuko Tanizaki;A. Kimura;Y. Ishida;M. Nosaka;S. Toujima;Y. Kuninaka;Sawako Minami;K. Ino;T. Kondo
卵巢癌是女性生殖器恶性肿瘤中癌症死亡的主要原因，需要开发新的治疗措施。肿瘤细胞的免疫逃逸和获得耐受性是肿瘤生长和发展的必要条件。免疫调节酶吲哚胺2,3-双加氧酶（IDO）在肿瘤中的过度表达对宿主免疫耐受至关重要。Janus-activated kinase-signal transducer and activator of transcription （JAK-STAT）通路参与多种肿瘤生物学过程。因此，我们研究了AG490（一种JAK2抑制剂）抑制STAT1对小鼠卵巢癌进展的影响。在体外研究中，IFN-γ处理上调OV2944-HM-1细胞中didomrna的表达并激活STAT1，而AG490处理通过抑制STAT1磷酸化显著抑制这一作用。在体内模型中，将OV2944-HM-1细胞腹腔/皮下移植到同基因免疫能力雌性小鼠体内。与对照组相比，AG490治疗显著抑制皮下肿瘤生长。同样，在腹腔内接种HM-1细胞的小鼠中，同样的处理显著提高了存活率，同时减少了腹腔内肿瘤的数量。实际上，在ag490处理的小鼠中，随着STAT1激活的减少，肿瘤内IDO表达被显著抑制。此外，在AG490处理的小鼠肿瘤微环境中，CD8+T细胞、M1巨噬细胞、NK细胞等抗肿瘤白细胞的积累明显被夸大，而调节性T细胞的相互减少。此外，抗肿瘤细胞因子如IL-1α、IL-1β和IL-12的表达在AG490处理的小鼠瘤内显著增强。综上所述，JAK/STAT信号通路可能是卵巢癌免疫治疗的良好分子靶点。
Ovarian cancer is the major cause of cancer death among female genital malignancies, and requires developing novel therapeutic measures. Immune escape and acquisition of tolerance by tumor cells are essential for cancer growth and progression. An immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO) overexpression in tumors is essential for host immune tolerance. Janus-activated kinase-signal transducer and activator of transcription (JAK–STAT) pathway is involved in various kinds of tumor biology. Thus, we examined the effects of STAT1 inhibition by AG490 (a JAK2 inhibitor) on ovarian cancer progression in mice. In vitro study, IFN-γ treatment up-regulatedIdomRNA expression with STAT1 activation in OV2944-HM-1 cells, whereas AG490 treatment significantly inhibited this effect with the suppression of STAT1 phosphorylation. In vivo model, OV2944-HM-1 cells were intraperitoneally/subcutaneously transplanted into syngeneic immunocompetent female mice. AG490 treatment significantly suppressed subcutaneous tumor growth, compared with control. Consistently, in mice intraperitoneally inoculated HM-1 cells, the same treatment significantly improved survival rate with the reduced number of intraperitoneal tumors. Actually, intratumoral IDO expression was significantly suppressed with the reduction of STAT1 activation in AG490-treated mice. Moreover, in tumor microenvironment of mice treated with AG490, the accumulation of anti-tumor leukocytes such as CD8+T-cells, M1 macrophages, and NK cells was apparently exaggerated with the reciprocal reduction of regulatory T cells. Furthermore, intratumoral expression of anti-tumor cytokines such as IL-1α, IL-1β and IL-12 expression was significantly enhanced in mice treated with AG490. Collectively, JAK/STAT signal pathways may be good molecular target for immunotherapy of ovarian cancer.