Acetylsalicylic acid inhibits the growth of melanoma tumors via SOX2-dependent-PAF-R-independent signaling pathway.
Acetylsalicylic acid inhibits the growth of melanoma tumors via SOX2-dependent-PAF-R-independent signaling pathway.
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乙酰水杨酸通过SOX2依赖性PAF-R非依赖性信号通路抑制黑色素瘤肿瘤的生长。
DOI：
10.18632/oncotarget.18326
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发表时间：
2017-07-25
期刊：
影响因子：
--
通讯作者：
Sahu RP
中科院分区：
文献类型：
--
作者：
Thyagarajan A;Saylae J;Sahu RP
对标准疗法的获得性耐药性仍然是一个严重的挑战，需要新的治疗方法，将涉及肿瘤耐药性的潜在因素。由于包括黑色素瘤在内的癌症表达炎性环氧合酶，产生与肿瘤生长有关的胰头素，我们研究了抗炎药物乙酰水杨酸（阿萨）的机制，该药物已显示出抑制各种肿瘤类型，然而，其对高度侵袭性黑色素瘤模型的作用尚不清楚。鉴于我们的报告，血小板活化因子受体（PAF-R）的激活增强了实验性黑色素瘤的生长，并阻碍了治疗药物的疗效，我们还试图确定PAF-R是否介导阿萨的抗黑色素瘤活性。目前使用稳定的PAF-R阳性（B16-PAFR）和阴性（B16-MSCV）鼠黑素瘤细胞以及PAF-R表达和缺陷小鼠进行的研究表明，阿萨通过绕过肿瘤或间质PAF-R信号传导抑制高度侵袭性B16 F10黑素瘤的体外和体内生长。在PAF-R阳性或阴性的人黑色素瘤和鼻咽癌细胞中观察到类似的ASA诱导作用。ASA诱导的细胞存活率降低和细胞凋亡增加的机制可被前列腺素F2 α（PGF 2 α）激动剂显著阻断。重要的是，B16肿瘤的PCR阵列和qRT-PCR分析显示阿萨治疗显著下调了SRY相关的高迁移率盒2（SOX 2）癌基因。有趣的是，PGF 2 α激动剂对SOX 2表达的调节和成纤维细胞生长因子1（FGF-1）的上调使黑色素瘤细胞免于ASA诱导的存活率降低和凋亡增加。此外，PGF 2 α受体拮抗剂AL 8810模拟ASA诱导的黑色素瘤细胞存活率降低，而PGF 2 α和FGF-1显著阻断了这种作用。这些发现表明阿萨通过SOX 2依赖性-PAF-R依赖性途径抑制侵袭性黑素瘤的生长。
Acquired resistance to standard therapies remains a serious challenge, requiring novel therapeutic approaches that incorporate potential factors involved in tumor resistance. As cancers including melanoma express inflammatory cyclooxygenases generating prostaglandins implicated in tumor growth, we investigated mechanism of anti-inflammatory drug, acetylsalicylic acid (ASA) which has been shown to inhibit various tumor types, however, its effects against highly aggressive melanoma model are unclear. Given our reports that an activation of platelet-activating factor-receptor (PAF-R) augments the growth and impede efficacies of therapeutic agents in experimental melanoma, we also sought to determine if PAF-R mediates anti-melanoma activity of ASA. The current studies using stably PAF-R-positive (B16-PAFR) and negative (B16-MSCV) murine melanoma cells and PAF-R-expressing and deficient mice, demonstrate that ASA inhibits the in-vitro and in-vivo growth of highly aggressive B16F10 melanoma via bypassing tumoral or stromal PAF-R signaling. Similar ASA-induced effects in-vitro were seen in human melanoma and nasopharyngeal carcinoma cells positive or negative in PAF-R. Mechanistically, the ASA-induced decrease in cell survival and increase in apoptosis were significantly blocked by prostaglandin F2 alpha (PGF2α) agonists. Importantly, PCR array and qRT-PCR analysis of B16-tumors revealed significant downregulation of sry-related high-mobility-box-2 (SOX2) oncogene by ASA treatment. Interestingly, modulation of SOX2 expression by PGF2α agonists and upregulation by fibroblast growth factor 1 (FGF-1) rescued melanoma cells from ASA-induced decreased survival and increased apoptosis. Moreover, PGF2α-receptor antagonist, AL8810 mimics ASA-induced decreased melanoma cells survival which was significantly blocked by PGF2α and FGF-1. These findings indicate that ASA inhibits the growth of aggressive melanoma via SOX2-dependent-PAF-R-indepedent pathway.
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影响因子：
5.7
作者：
Huang Y;Lichtenberger LM;Taylor M;Bottsford-Miller JN;Haemmerle M;Wagner MJ;Lyons Y;Pradeep S;Hu W;Previs RA;Hansen JM;Fang D;Dorniak PL;Filant J;Dial EJ;Shen F;Hatakeyama H;Sood AK
通讯作者：
Sood AK
DOI：
10.1083/jcb.200409182
发表时间：
2005-03-28
期刊：
The Journal of cell biology
影响因子：
--
作者：
Mansukhani A;Ambrosetti D;Holmes G;Cornivelli L;Basilico C
通讯作者：
Basilico C
影响因子：
4.4
作者：
Darst, M;Al-Hassani, M;Travers, JB
通讯作者：
Travers, JB
影响因子：
64.8
作者：
Boumahdi, Soufiane;Driessens, Gregory;Blanpain, Cedric
通讯作者：
Blanpain, Cedric
影响因子：
4.8
作者：
Li, T;Southall, MD;Travers, JB
通讯作者：
Travers, JB