Fenretinide combines perturbation of signaling kinases, cell-extracellular matrix interactions and matrix metalloproteinase activation to inhibit invasion in oral squamous cell carcinoma cells.
Fenretinide combines perturbation of signaling kinases, cell-extracellular matrix interactions and matrix metalloproteinase activation to inhibit invasion in oral squamous cell carcinoma cells.
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DOI：
10.1093/carcin/bgac070
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发表时间：
2022-10-22
期刊：
影响因子：
4.7
通讯作者：
中科院分区：
文献类型：
--
作者：
基底膜侵犯定义了表面癌前病变的恶变。用合成的维生素A衍生物芬维A胺（4 HPR）治疗口腔鳞状细胞癌（OSCC）细胞，诱导许多癌症预防作用，包括抑制基底膜侵袭、消除锚定非依赖性生长、破坏肌动蛋白细胞骨架成分和抑制侵袭性粘着斑激酶。本研究的目的是阐明4 HPR对其他侵袭相关机制的影响，包括基质金属蛋白酶（MMP）激活和功能，细胞-细胞外基质（ECM）附着以及与上皮-肌上皮转化所必需的激酶（即c-Jun NH 2-末端激酶（JNK））的相互作用。我们的数据显示，4 HPR结合与所有三个JNK亚型的ATP结合位点具有高亲和力，同时抑制激酶功能。进一步的研究表明，4 HPR处理抑制OSCC细胞-ECM粘附和MMP活化和功能。JNK下调和诱导表达的研究证实，JNK 3亚型传达了最大的影响，口腔鳞癌的迁移和侵袭。生物可降解的聚合物植入物，制定保留4 HPR的功能和生物利用度进行评估4 HPR的化学预防的影响，对口腔鳞状细胞癌肿瘤诱导模型。这些研究显示，4 HPR局部递送显著抑制OSCC肿瘤大小、有丝分裂指数和内皮标志物、成红细胞转化特异性相关基因的表达，同时增加肿瘤细胞凋亡（裂解的半胱天冬酶-3）。总的来说，这些数据显示4 HPR在多个位点抑制侵袭，包括“由外向内”信号传导、细胞-ECM相互作用和MMP的抑制。这些功能对于生理功能也是必不可少的。因此，监管是必不可少的，并加强了局部递送化学预防制剂的药理学优势。.侵袭是癌发生的中心过程。本研究首次报道了芬维A胺抑制侵袭的机制。采用控释生物可利用制剂的补充体内研究证实了芬维A胺的抗肿瘤特性，对正常组织无不良影响。
Basement membrane invasion defines malignant transformation of surface premalignancy. Treatment of oral squamous cell carcinoma (OSCC) cells with the synthetic vitamin A derivative, fenretinide (4HPR), induces numerous cancer-preventive effects including suppression of basement membrane invasion, elimination of anchorage-independent growth, disruption of actin cytoskeletal components and inhibition of the invasion-enabling focal adhesive kinase. The purpose of this study was to elucidate 4HPR’s effects on additional invasion-relevant mechanisms including matrix metalloproteinase (MMP) activation and function, cell–extracellular matrix (ECM) attachments and interaction with a kinase that is essential for the epithelial–myoepithelial transformation i.e. c-Jun NH2-terminal kinase (JNK). Our data revealed that 4HPR binds with high affinity to the ATP-binding site of all three JNK isoforms with concurrent suppression of kinase function. Additional studies showed 4HPR treatment inhibited both OSCC cell–ECM adhesion and MMP activation and function. JNK downregulation and induced expression studies confirmed that the JNK3 isoform conveyed that largest impact on OSCC migration and invasion. Biodegradable polymeric implants formulated to preserve 4HPR’s function and bioavailability were employed to assess 4HPR’s chemopreventive impact on an OSCC tumor induction model. These studies revealed 4HPR local delivery significantly inhibited OSCC tumor size, mitotic indices and expression of the endothelial marker, erythroblast transformation-specific-related gene with concurrent increases in tumor apoptosis (cleaved caspase-3). Collectively, these data show that 4HPR suppresses invasion at multiple sites including ‘outside-in’ signaling, cell–ECM interactions and suppression of MMPs. These functions are also essential for physiologic function. Regulation is therefore essential and reinforces the pharmacologic advantage of local delivery chemopreventive formulations. . Invasion is a central process in carcinogenesis. This study reports, for the first time, mechanisms by which fenretinide suppresses invasion. Complementary in vivostudies, that employed a controlled-release bioavailable formulation, confirmed fenretinide’s antitumorigenic properties without adverse effects to normal tissues.
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影响因子：
16.6
作者：
Horiuchi, Shinnosuke;Tachibana, Yuki;Yamashita, Mitsuki;Yamamoto, Koji;Masai, Kohei;Takase, Kohei;Matsutani, Teruo;Kawamata, Shiori;Kurashige, Yuki;Yanai, Takeshi;Murahashi, Tetsuro
通讯作者：
Murahashi, Tetsuro
影响因子：
0.3
作者：
Görögh, T;Berwig, J;Lippert, BM
通讯作者：
Lippert, BM
影响因子：
11.2
作者：
Liotta LA
通讯作者：
Liotta LA
DOI：
10.1158/1940-6207.capr-14-0418
发表时间：
2015-05
期刊：
Cancer prevention research (Philadelphia, Pa.)
影响因子：
--
作者：
Han BB;Li S;Tong M;Holpuch AS;Spinney R;Wang D;Border MB;Liu Z;Sarode S;Pei P;Schwendeman SP;Mallery SR
通讯作者：
Mallery SR
影响因子：
2.9
作者：
Krieger, E;Koraimann, G;Vriend, G
通讯作者：
Vriend, G