Dictyostelium Differentiation-Inducing Factor-1 Binds to Mitochondrial Malate Dehydrogenase and Inhibits Its Activity

Journal of Pharmacological Sciences

Toshiyuki Sasaguri²  Yuzuru Kubohara³  Fumi Takahashi-Yanaga²  Yoshikazu Miwa²  Sachio Morimoto²  Tomoko Matsuda²  Yutaka Watanabe¹  Katsumi Maenaka⁴  Masato Hirata⁵  Tatsuya Yoshihara² 

[1] Department of Applied Chemistry, Faculty of Engineering, Ehime University, Japan;Department of Clinical Pharmacology, Faculty of Medical Sciences, Kyushu University, Japan;Biosignal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, Japan;Medical Institute of Bioregulation, Kyushu University, Japan;Laboratory of Molecular and Cellular Biochemistry, Faculty of Dental Sciences, Kyushu University, Japan

关键词: differentiation-inducing factor;    mitochondrial malate dehydrogenase (mMDH);    energy production;    ATP content;    cell proliferation;   

DOI  :  10.1254/jphs.09348FP

学科分类：药学

来源: Nihon Yakuri Gakkai Henshuubu / Japanese Pharmacological Society

【 摘 要 】

References(26)Cited-By(5)We have reported that the differentiation-inducing factors (DIFs) DIF-1 and DIF-3, morphogens secreted from Dictyostelium discoideum, inhibit proliferation of several cancer cells via suppression of the Wnt/β-catenin signaling pathway. However, the target molecules of DIFs involved in the anti-proliferative effects are still unknown. In the present study, DIF-1–tethered resins were synthesized to explore the target molecules of DIFs, and mitochondrial malate dehydrogenase (mMDH) was identified as one of the target molecules. In the in vitro assay, DIF-1 and other analogs including 2-MIDIF-1, DIF-3, and 6-MIDIF-3 were found to be capable of binding to mMDH but not to cytoplasmic MDH. However, only DIF-1 and 2-MIDIF-1 inhibited the enzymatic activity of mMDH. The effects of DIF analogs on ATP content and cell proliferation were then analyzed using HeLa cells. DIF-1 and 2-MIDIF-1 were found to lower the ATP content and both chemicals inhibited HeLa cell proliferation, suggesting that inhibition of mMDH activity affected cell energy production, probably leading to the inhibition of proliferation. These results suggest that the inhibition of mMDH activity by DIF-1 and 2-MIDIF-1 could be one of the mechanisms to induce anti-proliferative effects, independent of the inhibition of the Wnt/β-catenin signaling pathway.

【 授权许可】

Unknown