論文種別	原著(症例報告除く)
言語種別	英語
査読の有無	その他(不明)
表題	Inhibition of glycolysis and stimulation of mitochondrial biogenesis lead to increased ROS levels and cell death in HNF-1ß positive clear cell carcinoma.
掲載誌名	正式名：Cell death & disease 略　 称：Cell Death Dis ISSNコード：20414889
掲載区分	国外
巻・号・頁	16(1),pp.879
著者・共著者	Naoki Kawahara, Hiroki Kuniyasu, Shiori Mori, Shingo Kishi, Sumire Sugimoto, Tomoka Maehana, Shoichiro Yamanaka, Ryuji Kawaguchi, Fuminori Kimura
発行年月	2025/12
概要	Ovarian clear cell carcinoma is characterized by HNF-1ß overexpression and is known to be resistant to chemotherapy. An inhibitor screening that specifically targets HNF-1ß led us to identify Actinonin as a candidate for cancer treatment. Actinonin, which is known to inhibit aminopeptidase M, has also been recognized for its antibacterial properties. We confirmed that GSK-3ß interference/inhibition, as a component of the HNF-1ß pathway, combined with Actinonin, has a highly potent antitumor effect compared to monotherapy. The same effect was observed in renal clear cell carcinoma lines expressing HNF-1ß. Actinonin promoted mitochondrial production by suppressing aerobic respiration, which decreased AMPK levels and increased ROS production. However, it also elevated GADD45α expression and induced mitophagy. GSK-3ß inhibition suppressed glycolysis and shifted energy production to OXPHOS, leading to increased ROS production. Furthermore, this combination produced excess ROS beyond metabolic capacity, which accumulated in lipid bilayers, leading to a further increase in CHOP gene expression and suppression of mitochondrial turnover. The GSK-3ß inhibitor and Actinonin combination demonstrated a powerful tumor-suppressive effect in vivo without severe side effects. Combining GSK-3ß inhibition with Actinonin can effectively eliminate cancer cells with HNF-1ß overexpression by inhibiting glycolysis and promoting mitochondrial turnover, highlighting new options for cancer therapy.
DOI	10.1038/s41419-025-08243-2
PMID	41326368