Tanaka Noritaka, Sakamoto Takeharu
Department of Cancer Biology, Institute of Biomedical Science, Kansai Medical University; 2-5-1 Shin-machi, Hirakata 573-1010, Osaka, Japan.
Biomedicines. 2023 Feb 14;11(2):549. doi: 10.3390/biomedicines11020549.
Hypoxia-inducible factor-1α (HIF-1α) is a transcription factor that plays a crucial role in cells adapting to a low-oxygen environment by facilitating a switch from oxygen-dependent ATP production to glycolysis. Mediated by membrane type-1 matrix metalloproteinase (MT1-MMP) expression, Munc-18-1 interacting protein 3 (Mint3) binds to the factor inhibiting HIF-1 (FIH-1) and inhibits its suppressive effect, leading to HIF-1α activation. Defects in Mint3 generally lead to improved acute inflammation, which is regulated by HIF-1α and subsequent glycolysis, as well as the suppression of the proliferation and metastasis of cancer cells directly through its expression in cancer cells and indirectly through its expression in macrophages or fibroblasts associated with cancer. Mint3 in inflammatory monocytes enhances the chemotaxis into metastatic sites and the production of vascular endothelial growth factors, which leads to the expression of E-selectin at the metastatic sites and the extravasation of cancer cells. Fibroblasts express L1 cell adhesion molecules in a Mint3-dependent manner and enhance integrin-mediated cancer progression. In pancreatic cancer cells, Mint3 directly promotes cancer progression. Naphthofluorescein, a Mint3 inhibitor, can disrupt the interaction between FIH-1 and Mint3 and potently suppress Mint3-mediated inflammation, cancer progression, and metastasis without causing marked adverse effects. In this review, we will introduce the potential of Mint3 as a therapeutic target for inflammatory diseases and cancers.
缺氧诱导因子-1α（HIF-1α）是一种转录因子，通过促进细胞从依赖氧气的ATP生成转变为糖酵解，在细胞适应低氧环境中发挥关键作用。在膜型-1基质金属蛋白酶（MT1-MMP）表达的介导下，Munc-18-1相互作用蛋白3（Mint3）与抑制HIF-1的因子（FIH-1）结合并抑制其抑制作用，从而导致HIF-1α激活。Mint3缺陷通常会导致急性炎症改善，急性炎症由HIF-1α和随后的糖酵解调节，并且通过其在癌细胞中的表达直接以及通过其在与癌症相关的巨噬细胞或成纤维细胞中的表达间接抑制癌细胞的增殖和转移。炎症单核细胞中的Mint3增强了向转移部位的趋化性和血管内皮生长因子的产生，这导致转移部位E-选择素的表达和癌细胞的外渗。成纤维细胞以Mint3依赖的方式表达L1细胞粘附分子，并增强整合素介导的癌症进展。在胰腺癌细胞中，Mint3直接促进癌症进展。萘荧光素是一种Mint3抑制剂，可破坏FIH-1与Mint3之间的相互作用，并有效抑制Mint3介导的炎症、癌症进展和转移，而不会引起明显的不良反应。在这篇综述中，我们将介绍Mint3作为炎症性疾病和癌症治疗靶点的潜力。
