Pharmacological inhibition of Mint3 attenuates tumour growth, metastasis, and endotoxic shock
| Autor: | Yuya Fukui, Yasumitsu Kondoh, Jun-ichiro Inoue, Yurika Saitoh, Takeharu Sakamoto, Shuichi Kaneko, Motoharu Seiki, Hiroyuki Osada, Takeshi Shimizu, Toshiro Hara, Yoshinori Murakami, Kaori Honda, Tetsuro Hayashi |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Carcinogenesis
QH301-705.5 medicine.medical_treatment Medicine (miscellaneous) General Biochemistry Genetics and Molecular Biology Article Metastasis Mixed Function Oxygenases In vivo Cell Line Tumor Neoplasms Medicine Humans Glycolysis Neoplasm Metastasis Biology (General) Adaptor Proteins Signal Transducing Cancer business.industry medicine.disease Fluoresceins Hypoxia-Inducible Factor 1 alpha Subunit Shock Septic In vitro Repressor Proteins Cytokine Cancer cell Cancer research General Agricultural and Biological Sciences business Homeostasis |
| Zdroj: | Communications Biology, Vol 4, Iss 1, Pp 1-15 (2021) Communications Biology |
| ISSN: | 2399-3642 |
| Popis: | Hypoxia-inducible factor-1 (HIF-1) plays essential roles in human diseases, though its central role in oxygen homoeostasis hinders the development of direct HIF-1-targeted pharmacological approaches. Here, we surveyed small-molecule compounds that efficiently inhibit the transcriptional activity of HIF-1 without affecting body homoeostasis. We focused on Mint3, which activates HIF-1 transcriptional activity in limited types of cells, such as cancer cells and macrophages, by suppressing the factor inhibiting HIF-1 (FIH-1). We identified naphthofluorescein, which inhibited the Mint3–FIH-1 interaction in vitro and suppressed Mint3-dependent HIF-1 activity and glycolysis in cancer cells and macrophages without evidence of cytotoxicity in vitro. In vivo naphthofluorescein administration suppressed tumour growth and metastasis without adverse effects, similar to the genetic depletion of Mint3. Naphthofluorescein attenuated inflammatory cytokine production and endotoxic shock in mice. Thus, Mint3 inhibitors may present a new targeted therapeutic option for cancer and inflammatory diseases by avoiding severe adverse effects. Sakomoto et al. identify naphthofluorescein as a mint3 inhibitor that disrupts the Mint3–FIH-1 interaction and attenuates HIF-1 activity. In vivo experiments in mice reveal a reduction in tumor growth with attenuated inflammatory cytokine production and endotoxic shock, presenting an option for targeted therapies for cancer and inflammatory diseases that avoid severe adverse effects. |
| Databáze: | OpenAIRE |
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