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Yuzuru Kubohara - One of the best experts on this subject based on the ideXlab platform.

  • Dictyostelium Differentiation-Inducing Factor-1 Promotes Glucose Uptake, at Least in Part, via an AMPK-Dependent Pathway in Mouse 3T3-L1 Cells.
    International journal of molecular sciences, 2021
    Co-Authors: Yuzuru Kubohara, Yoshiteru Oshima, Yoshimi Homma, Hiroshi Shibata, Haruhisa Kikuchi
    Abstract:

    Differentiation-Inducing Factor-1 (DIF-1) is a chlorinated alkylphenone (a polyketide) found in the cellular slime mold Dictyostelium discoideum. DIF-1 and its derivative, DIF-1(3M) promote glucose consumption in vitro in mammalian cells and in vivo in diabetic rats; they are expected to be the leading antiobesity and antidiabetes compounds. In this study, we investigated the mechanisms underlying the actions of DIF-1 and DIF-1(3M). In isolated mouse liver mitochondria, these compounds at 2–20 mM promoted oxygen consumption in a dose-dependent manner, suggesting that they act as mitochondrial uncouplers, whereas CP-DIF-1 (another derivative of DIF-1) at 10–20 mM had no effect. In confluent mouse 3T3-L1 fibroblasts, DIF-1 and DIF-1(3M) but not CP-DIF-1 induced phosphorylation (and therefore activation) of AMP kinase (AMPK) and promoted glucose consumption and metabolism. The DIF-induced glucose consumption was reduced by compound C (an AMPK inhibitor) or AMPK knock down. These data suggest that DIF-1 and DIF-1(3M) promote glucose uptake, at least in part, via an AMPK-dependent pathway in 3T3-L1 cells, whereas cellular metabolome analysis revealed that DIF-1 and DIF-1(3M) may act differently at least in part.

  • Halogen-Substituted Derivatives of Dictyostelium Differentiation-Inducing Factor-1 Suppress Serum-Induced Cell Migration of Human Breast Cancer MDA-MB-231 Cells in Vitro.
    Biomolecules, 2019
    Co-Authors: Kyoko Totsuka, Katsunori Takahashi, Haruhisa Kikuchi, Yoshiteru Oshima, Yuka Makioka, Kyoichi Iizumi, Yuzuru Kubohara
    Abstract:

    Triple-negative breast cancer (TNBC) is highly proliferative and metastatic, and because it lacks three major molecular targets for chemotherapy (estrogen receptor, progesterone receptor, and human epidermal receptor 2), it is extremely refractory. Differentiation-Inducing Factor 1 (DIF-1) and DIF-3, which are chlorinated alkylphenones, are lead anticancer compounds found in the cellular slime mold Dictyostelium discoideum. Here, we examined the in vitro effects of DIF-1, DIF-3, and 25 DIF derivatives on cell proliferation and serum-induced cell migration in human MDA-MB-231 cells, a model TNBC cell line. We found that Br-DIF-1, a chlorine-to-bromine-substituted derivative of DIF-1, strongly suppressed cell migration (IC50, 3.8 M) with negligible effects on cell proliferation (IC50, >20 M). We then synthesized 18 derivatives of Br-DIF-1 and examined the in vitro effects of these derivatives on cell proliferation and serum-induced cell migration in MDA-MB-231 cells. Among the derivatives, Br-DIF-1(+1), Br-DIF-1(+2), and Br-DIF-3(+2) exhibited strong anti-cell migration activities with IC50 values of 1.5, 1.0, and 3.1 M, respectively, without affecting cell proliferation (IC50, >20 M). These results suggest that these Br-DIF derivatives are good lead compounds for the development of anti-metastatic drugs against TNBC.

  • Evidence that Differentiation-Inducing Factor-1 controls chemotaxis and cell Differentiation, at least in part, via mitochondria in D. discoideum
    The Company of Biologists, 2017
    Co-Authors: Yuzuru Kubohara, Haruhisa Kikuchi, Hidekazu Kuwayama, Van Hai Nguyen, Yoshiteru Oshima
    Abstract:

    Differentiation-Inducing Factor-1 [1-(3,5-dichloro-2,6-dihydroxy-4-methoxyphenyl)hexan-1-one (DIF-1)] is an important regulator of cell Differentiation and chemotaxis in the development of the cellular slime mold Dictyostelium discoideum. However, the entire signaling pathways downstream of DIF-1 remain to be elucidated. To characterize DIF-1 and its potential receptor(s), we synthesized two fluorescent derivatives of DIF-1, boron-dipyrromethene (BODIPY)-conjugated DIF-1 (DIF-1-BODIPY) and nitrobenzoxadiazole (NBD)-conjugated DIF-1 (DIF-1-NBD), and investigated their biological activities and cellular localization. DIF-1-BODIPY (5 µM) and DIF-1 (2 nM) induced stalk cell Differentiation in the DIF-deficient strain HM44 in the presence of cyclic adenosine monosphosphate (cAMP), whereas DIF-1-NBD (5 µM) hardly induced stalk cell Differentiation under the same conditions. Microscopic analyses revealed that the biologically active derivative, DIF-1-BODIPY, was incorporated by stalk cells at late stages of Differentiation and was localized to mitochondria. The mitochondrial uncouplers carbonyl cyanide m-chlorophenylhydrazone (CCCP), at 25–50 nM, and dinitrophenol (DNP), at 2.5–5 µM, induced partial stalk cell Differentiation in HM44 in the presence of cAMP. DIF-1-BODIPY (1–2 µM) and DIF-1 (10 nM), as well as CCCP and DNP, suppressed chemotaxis in the wild-type strain Ax2 in shallow cAMP gradients. These results suggest that DIF-1-BODIPY and DIF-1 induce stalk cell Differentiation and modulate chemotaxis, at least in part, by disturbing mitochondrial activity

  • Biological Activities of Novel Derivatives of Differentiation-Inducing Factor 3 from Dictyostelium discoideum.
    Biological & pharmaceutical bulletin, 2017
    Co-Authors: Katsunori Takahashi, Haruhisa Kikuchi, Yoshiteru Oshima, Van Hai Nguyen, Hirotaka Ishigaki, Junko Nakajima-shimada, Yuzuru Kubohara
    Abstract:

    Differentiation-Inducing Factor-3 (DIF-3; 1-(3-chloro-2,6-dihydroxy-4-methoxyphenyl)hexan-1-one), which is found in the cellular slime mold Dictyostelium discoideum, is a potential candidate compound for the development of new medicines; DIF-3 and its derivatives possess several beneficial biological activities, including anti-tumor, anti-Trypanosoma cruzi, and immunoregulatory effects. To assess the relationship between the biological activities of DIF-3 and its chemical structure, particularly in regard to its alkoxy group and the length of the alkyl chains at the acyl group, we synthesized two derivatives of DIF-3, 1-(3-chloro-2,6-dihydroxy-4-methoxyphenyl)octan-1-one (DIF-3(+3)) and 1-(3-chloro-2,6-dihydroxy-4-butoxyphenyl)-hexan-1-one (Hex-DIF-3), and investigated their biological activities in vitro. At micro-molar levels, DIF-3(+3) and Hex-DIF-3 exhibited strong anti-proliferative effects in tumor cell cultures, but their anti-T. cruzi activities at 1 µM in vitro were not as strong as those of other known DIF derivatives. In addition, Hex-DIF-3 at 5 µM significantly suppressed mitogen-induced interleukin-2 production in vitro in Jurkat T cells. These results suggest that DIF-3(+3) and Hex-DIF-3 are promising leads for the development of anti-cancer and immunosuppressive agents.

  • Oral administration of Dictyostelium Differentiation-Inducing Factor 1 lowers blood glucose levels in streptozotocin-induced diabetic rats.
    Life sciences, 2016
    Co-Authors: Ritsuko Kawaharada, Katsunori Takahashi, Haruhisa Kikuchi, Yoshiteru Oshima, Akio Nakamura, Yuzuru Kubohara
    Abstract:

    Abstract Aims Differentiation-Inducing Factor 1 (DIF-1), originally discovered in the cellular slime mold Dictyostelium discoideum , and its derivatives possess pharmacological activities, such as the promotion of glucose uptake in non-transformed mammalian cells in vitro . Accordingly, DIFs are considered promising lead candidates for novel anti-diabetic drugs. The aim of this study was to assess the anti-diabetic and toxic effects of DIF-1 in mouse 3T3-L1 fibroblast cells in vitro and in diabetic rats in vivo . Main methods We investigated the in vitro effects of DIF-1 and DIF-1(3M), a derivative of DIF-1, on glucose metabolism in 3T3-L1 cells by using capillary electrophoresis time-of-flight mass spectrometry (CE-TOF-MS). We also examined the effects of DIF-1 on blood glucose levels in streptozotocin (STZ)-induced rats. Key findings . CE-TOF-MS revealed that 20 μM DIF-1 and 20 μM DIF-1(3M) promoted glucose uptake and metabolism in 3T3-L1 cells. Oral administration of DIF-1 (30 mg/kg) significantly lowered basal blood glucose levels in STZ-treated rats and promoted a decrease in blood glucose levels after oral glucose loading (2.5 g/kg) in the rats. In addition, daily oral administration of DIF-1 (30 mg/kg/day) for 1 wk significantly lowered the blood glucose levels in STZ-treated rats but did not affect their body weight and caused only minor alterations in the levels of other blood analytes. Significance These results indicate that DIF-1 may be a good lead compound for the development of anti-diabetic drugs.

Toshiyuki Sasaguri - One of the best experts on this subject based on the ideXlab platform.

  • Differentiation-Inducing Factor-1 suppresses cyclin D1-induced cell proliferation of MCF-7 breast cancer cells by inhibiting S6K-mediated signal transducer and activator of transcription 3 synthesis
    Cancer science, 2019
    Co-Authors: Fumi Tetsuo, Fumi Takahashi-yanaga, Masaki Arioka, Kazunobu Igawa, Katsuhiko Tomooka, Koichi Miura, Misato Kai, Momoko Kubo, Fusanori Nishimura, Toshiyuki Sasaguri
    Abstract:

    Differentiation-Inducing Factor-1 (DIF-1) has been reported to inhibit the proliferation of various mammalian cells by unknown means, although some possible mechanisms of its action have been proposed, including the activation of glycogen synthase kinase-3 (GSK-3). Here, we report an alternative mechanism underlying the action of DIF-1 in human breast cancer cell line MCF-7, on which the effects of DIF-1 have not been examined previously. Intragastric administration of DIF-1 reduced the tumor growth from MCF-7 cells injected into a mammary fat pad of nude mice, without causing adverse effects. In cultured MCF-7, DIF-1 arrested the cell cycle in G0 /G1 phase and suppressed cyclin D1 expression, consistent with our previous results obtained in other cell species. However, DIF-1 did not inhibit the phosphorylation of GSK-3. Investigating an alternative mechanism for the reduction of cyclin D1, we found that DIF-1 reduced the protein levels of signal transducer and activator of transcription 3 (STAT3). The STAT3 inhibitor S3I-201 suppressed cyclin D1 expression and cell proliferation and the overexpression of STAT3 enhanced cyclin D1 expression and accelerated proliferation. Differentiation-Inducing Factor-1 did not reduce STAT3 mRNA or reduce STAT3 protein in the presence of cycloheximide, suggesting that DIF-1 inhibited STAT3 protein synthesis. Seeking its mechanism, we revealed that DIF-1 inhibited the activation of 70 kDa and/or 85 kDa ribosomal protein S6 kinase (p70S6K /p85S6K ). Inhibition of p70S6K /p85S6K by rapamycin also reduced the expressions of STAT3 and cyclin D1. Therefore, DIF-1 suppresses MCF-7 proliferation by inhibiting p70S6K /p85S6K activity and STAT3 protein synthesis followed by reduction of cyclin D1 expression.

  • Anti-cancer effects of Differentiation-Inducing Factor-1 in triple negative breast cancer
    Annals of Oncology, 2019
    Co-Authors: Fumi Tetsuo, Masaki Arioka, Fusanori Nishimura, F.y. Takahashi, Toshiyuki Sasaguri
    Abstract:

    Abstract Background Breast cancer is the most common cancer in women and its metastasis markedly exacerbates patients’ prognosis. In particular, triple negative breast cancer (TNBC), which lacks estrogen receptors (ER), progesterone receptors (PR) and human epidermal growth Factor receptor 2 (HER2), is an aggressive subtype of breast cancer frequently forming metastatic lesions. Differentiation-Inducing Factor-1 (DIF-1) identified in Dictyostelium discoideum inhibits cell proliferation and migration of various mammalian cancer cells. However, the effect of DIF-1 on TNBC has not been examined. Here, we investigated whether DIF-1 shows anti-proliferative and anti-metastatic effects on TNBC by in-vivo and in-vitro experiments. Methods In in-vivo experiments, we used cancer xenograft model mice in which murine TNBC 4T1/Luc cells (1.0 × 106 cells/mL) were injected into mammary fat pads to evaluate the effects of intragastric administration of DIF-1 (300 mg/kg/day) on the primary tumor growth and lung metastasis. In in-vitro experiments, we carried out assays for cell proliferation, migration and invasion to evaluate the anti-proliferative and anti-metastatic effects of DIF-1. We also conducted Western blotting and real-time RT-PCR to identify the mechanisms for DIF-1’s anti-cancer effects. Results In vivo, administration of DIF-1 significantly suppressed the primary tumor growth and lung metastasis without adverse effects such as weight loss and myelosuppression. In vitro, DIF-1 reduced cyclin D1 and c-Myc by inhibiting transcription and promoting degradation of the proteins, which resulted in the suppression of cell proliferation. DIF-1 also suppressed cell migration and invasion and reduced the protein expressions of snail, twist, vimentin and MMP-2, crucial Factors in epithelial-mesenchymal transition (EMT). Conclusions DIF-1 exerts anti-cancer effects in TNBC by reducing cell cycle accelerators and reversing EMT. Our findings suggest that using DIF-1 as a lead compound could develop a novel anti-cancer agent for TNBC. Legal entity responsible for the study The study protocol was approved by the Committee on Ethics of Animal Experiments of Kyushu University. Animal handling and procedures were carried out in compliance with the Guidelines for Animal Experiments, Kyushu University, and the Law (No. 105) and Notification (No. 6) of the Japanese Government. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

  • Anti-tumor effects of Differentiation-Inducing Factor-1 in malignant melanoma: GSK-3-mediated inhibition of cell proliferation and GSK-3-independent suppression of cell migration and invasion.
    Biochemical pharmacology, 2017
    Co-Authors: Masaki Arioka, Fumi Takahashi-yanaga, Kazunobu Igawa, Katsuhiko Tomooka, Momoko Kubo, Toshiyuki Sasaguri
    Abstract:

    Differentiation-Inducing Factor-1 (DIF-1) isolated from Dictyostelium discoideum strongly inhibits the proliferation of various mammalian cells through the activation of glycogen synthase kinase-3 (GSK-3). To evaluate DIF-1 as a novel anti-cancer agent for malignant melanoma, we examined whether DIF-1 has anti-proliferative, anti-migratory, and anti-invasive effects on melanoma cells using in vitro and in vivo systems. DIF-1 reduced the expression levels of cyclin D1 and c-Myc by facilitating their degradation via GSK-3 in mouse (B16BL6) and human (A2058) malignant melanoma cells, and thereby strongly inhibited their proliferation. DIF-1 suppressed the canonical Wnt signaling pathway by lowering the expression levels of transcription Factor 7-like 2 and β-catenin, key transcription Factors in this pathway. DIF-1 also inhibited cell migration and invasion, reducing the expression of matrix metalloproteinase-2; however, this effect was not dependent on GSK-3 activity. In a mouse lung tumor formation model, repeated oral administrations of DIF-1 markedly reduced melanoma colony formation in the lung. These results suggest that DIF-1 inhibits cell proliferation by a GSK-3-dependent mechanism and suppresses cell migration and invasion by a GSK-3-independent mechanism. Therefore, DIF-1 may have a potential as a novel anti-cancer agent for the treatment of malignant melanoma.

  • Differentiation-Inducing Factor-1 suppresses the expression of c-Myc in the human cancer cell lines.
    Journal of pharmacological sciences, 2013
    Co-Authors: Kentaro Jingushi, Fumi Takahashi-yanaga, Tatsuya Yoshihara, Sachio Morimoto, Yutaka Watanabe, Toshihisa Nakamura, Etsuko Matsuzaki, Toshiyuki Sasaguri
    Abstract:

    Differentiation-Inducing Factor-1 (DIF-1), a morphogen for Dictyostelium discoideum, inhibits the proliferation of human cancer cell lines by suppressing the Wnt/β-catenin signaling pathway. In this study, we examined the effect of DIF-1 on c-Myc, a target gene product of the Wnt/β-catenin signaling pathway, mainly using HCT-116 colon cancer cells. DIF-1 strongly reduced the amount of c-Myc protein in time- and concentration-dependent manners and reduced c-Myc mRNA expression by inhibiting promoter activity through the TCF binding sites. The effect of DIF-1 on c-Myc was also confirmed using the human cervical cell line HeLa. Pretreatment with the proteasome inhibitor MG132 or glycogen synthase kinase-3β (GSK-3β) inhibitors (LiCl and SB216763) attenuated the effect of DIF-1, suggesting that DIF-1 induced c-Myc protein degradation through GSK-3β activation. Furthermore, we examined whether c-Myc was involved in the anti-proliferative effect of DIF-1 using c-Myc-overexpressing cells and found that c-Myc was associated with the anti-proliferative effect of this compound. These results suggest that DIF-1 inhibits c-Myc expression by inhibiting promoter activity and Inducing protein degradation via GSK-3β activation, resulting in the inhibition of cell proliferation. Since c-Myc seems to be profoundly involved in accelerated proliferation of various malignant tumors, DIF-1 may have a potential to develop into a novel anti-cancer agent.

  • Anti-angiogenic effects of Differentiation-Inducing Factor-1 involving VEGFR-2 expression inhibition independent of the Wnt/β-catenin signaling pathway.
    Molecular cancer, 2010
    Co-Authors: Tatsuya Yoshihara, Fumi Takahashi-yanaga, Sachio Morimoto, Masato Hirata, Yutaka Watanabe, Fumie Shiraishi, Sumio Hoka, Toshiyuki Sasaguri
    Abstract:

    Background Differentiation-Inducing Factor-1 (DIF-1) is a putative morphogen that induces cell Differentiation in Dictyostelium discoideum. DIF-1 inhibits proliferation of various mammalian tumor cells by suppressing the canonical Wnt/β-catenin signaling pathway. To assess the potential of a novel cancer chemotherapy based on the pharmacological effect of DIF-1, we investigated whether DIF-1 exhibits anti-angiogenic effects in vitro and in vivo.

Fumi Takahashi-yanaga - One of the best experts on this subject based on the ideXlab platform.

  • Differentiation-Inducing Factor-1 potentiates adipogenic Differentiation and attenuates the osteogenic Differentiation of bone marrow-derived mesenchymal stem cells.
    Biochimica et biophysica acta. Molecular cell research, 2020
    Co-Authors: Shin Ishikane, Katsuhiko Tomooka, Kazunobu Igawa, Eigo Ikushima, Fumi Takahashi-yanaga
    Abstract:

    Abstract Mesenchymal stem cells (MSCs) are an attractive cell source for tissue regeneration and repair. However, their low Differentiation efficacy currently impedes the development of MSC therapy. Therefore, in this study, we investigated the effects of Differentiation-Inducing Factor-1 (DIF-1) on the Differentiation efficacy of bone marrow-derived MSCs (BM-MSCs) into adipogenic or osteogenic lineages. BM-MSCs, which were obtained from Sprague-Dawley rats, were positive for the MSC markers (CD29, CD73, and CD90). DIF-1 alone neither affected cell surface antigen expression nor induced adipogenic or osteogenic Differentiation. However, DIF-1 significantly enhanced the effects of adipogenic Differentiation stimuli, which were evaluated as the number of oil red-O positive cells and the expression of adipocyte Differentiation markers (peroxisome proliferator-activated receptor gamma, adipocyte fatty acid-binding protein, and adiponectin). In contrast, DIF-1 significantly attenuated the effects of osteogenic Differentiation stimuli, which were evaluated as alizarin red-S positive calcium deposition, and the expression of osteoblast Differentiation markers alkaline phosphatase, runt-related transcription Factor 2, and osteopontin. We further investigated the mechanism by which DIF-1 affects MSC Differentiation efficacy and found that glycogen synthase kinase-3 was the main Factor mediating the action of DIF-1 on the adipogenic Differentiation of BM-MSCs, whereas it was only partially involved in osteogenic Differentiation. These results suggest that DIF-1 supports MSC Differentiation toward the desired cell fate by enhancing the Differentiation efficacy.

  • Differentiation-Inducing Factor-1 suppresses cyclin D1-induced cell proliferation of MCF-7 breast cancer cells by inhibiting S6K-mediated signal transducer and activator of transcription 3 synthesis
    Cancer science, 2019
    Co-Authors: Fumi Tetsuo, Fumi Takahashi-yanaga, Masaki Arioka, Kazunobu Igawa, Katsuhiko Tomooka, Koichi Miura, Misato Kai, Momoko Kubo, Fusanori Nishimura, Toshiyuki Sasaguri
    Abstract:

    Differentiation-Inducing Factor-1 (DIF-1) has been reported to inhibit the proliferation of various mammalian cells by unknown means, although some possible mechanisms of its action have been proposed, including the activation of glycogen synthase kinase-3 (GSK-3). Here, we report an alternative mechanism underlying the action of DIF-1 in human breast cancer cell line MCF-7, on which the effects of DIF-1 have not been examined previously. Intragastric administration of DIF-1 reduced the tumor growth from MCF-7 cells injected into a mammary fat pad of nude mice, without causing adverse effects. In cultured MCF-7, DIF-1 arrested the cell cycle in G0 /G1 phase and suppressed cyclin D1 expression, consistent with our previous results obtained in other cell species. However, DIF-1 did not inhibit the phosphorylation of GSK-3. Investigating an alternative mechanism for the reduction of cyclin D1, we found that DIF-1 reduced the protein levels of signal transducer and activator of transcription 3 (STAT3). The STAT3 inhibitor S3I-201 suppressed cyclin D1 expression and cell proliferation and the overexpression of STAT3 enhanced cyclin D1 expression and accelerated proliferation. Differentiation-Inducing Factor-1 did not reduce STAT3 mRNA or reduce STAT3 protein in the presence of cycloheximide, suggesting that DIF-1 inhibited STAT3 protein synthesis. Seeking its mechanism, we revealed that DIF-1 inhibited the activation of 70 kDa and/or 85 kDa ribosomal protein S6 kinase (p70S6K /p85S6K ). Inhibition of p70S6K /p85S6K by rapamycin also reduced the expressions of STAT3 and cyclin D1. Therefore, DIF-1 suppresses MCF-7 proliferation by inhibiting p70S6K /p85S6K activity and STAT3 protein synthesis followed by reduction of cyclin D1 expression.

  • Anti-tumor effects of Differentiation-Inducing Factor-1 in malignant melanoma: GSK-3-mediated inhibition of cell proliferation and GSK-3-independent suppression of cell migration and invasion.
    Biochemical pharmacology, 2017
    Co-Authors: Masaki Arioka, Fumi Takahashi-yanaga, Kazunobu Igawa, Katsuhiko Tomooka, Momoko Kubo, Toshiyuki Sasaguri
    Abstract:

    Differentiation-Inducing Factor-1 (DIF-1) isolated from Dictyostelium discoideum strongly inhibits the proliferation of various mammalian cells through the activation of glycogen synthase kinase-3 (GSK-3). To evaluate DIF-1 as a novel anti-cancer agent for malignant melanoma, we examined whether DIF-1 has anti-proliferative, anti-migratory, and anti-invasive effects on melanoma cells using in vitro and in vivo systems. DIF-1 reduced the expression levels of cyclin D1 and c-Myc by facilitating their degradation via GSK-3 in mouse (B16BL6) and human (A2058) malignant melanoma cells, and thereby strongly inhibited their proliferation. DIF-1 suppressed the canonical Wnt signaling pathway by lowering the expression levels of transcription Factor 7-like 2 and β-catenin, key transcription Factors in this pathway. DIF-1 also inhibited cell migration and invasion, reducing the expression of matrix metalloproteinase-2; however, this effect was not dependent on GSK-3 activity. In a mouse lung tumor formation model, repeated oral administrations of DIF-1 markedly reduced melanoma colony formation in the lung. These results suggest that DIF-1 inhibits cell proliferation by a GSK-3-dependent mechanism and suppresses cell migration and invasion by a GSK-3-independent mechanism. Therefore, DIF-1 may have a potential as a novel anti-cancer agent for the treatment of malignant melanoma.

  • Differentiation-Inducing Factor-3 inhibits intestinal tumor growth in vitro and in vivo
    Journal of pharmacological sciences, 2015
    Co-Authors: Naoya Kubokura, Fumi Takahashi-yanaga, Masaki Arioka, Tatsuya Yoshihara, Kazunobu Igawa, Katsuhiko Tomooka, Sachio Morimoto, Yoshimichi Nakatsu, Teruhisa Tsuzuki, Yusaku Nakabeppu
    Abstract:

    Abstract Differentiation-Inducing Factor-1 (DIF-1) produced by Dictyostelium discoideum strongly inhibits the proliferation of various types of cancer cells by suppression of the Wnt/β-catenin signal transduction pathway. In the present study, we examined the effect of Differentiation-Inducing Factor-3 (DIF-3), a monochlorinated metabolite of DIF-1 that is also produced by D. discoideum, on human colon cancer cell lines HCT-116 and DLD-1. DIF-3 strongly inhibited cell proliferation by arresting the cell cycle at the G0/G1 phase. DIF-3 reduced the expression levels of cyclin D1 and c-Myc by facilitating their degradation via activation of GSK-3β in a time and dose-dependent manner. In addition, DIF-3 suppressed the expression of T-cell Factor 7-like 2, a key transcription Factor in the Wnt/β-catenin signaling pathway, thereby reducing the mRNA levels of cyclin D1 and c-Myc. Subsequently, we examined the in vivo effects of DIF-3 in Mutyh−/− mice with oxidative stress-induced intestinal cancers. Repeated oral administration of DIF-3 markedly reduced the number and size of cancers at a level comparable to that of DIF-1. These data suggest that DIF-3 inhibits intestinal cancer cell proliferation in vitro and in vivo, probably by mechanisms similar to those identified in DIF-1 actions, and that DIF-3 may be a potential novel anti-cancer agent.

  • Differentiation-Inducing Factor-1 suppresses the expression of c-Myc in the human cancer cell lines.
    Journal of pharmacological sciences, 2013
    Co-Authors: Kentaro Jingushi, Fumi Takahashi-yanaga, Tatsuya Yoshihara, Sachio Morimoto, Yutaka Watanabe, Toshihisa Nakamura, Etsuko Matsuzaki, Toshiyuki Sasaguri
    Abstract:

    Differentiation-Inducing Factor-1 (DIF-1), a morphogen for Dictyostelium discoideum, inhibits the proliferation of human cancer cell lines by suppressing the Wnt/β-catenin signaling pathway. In this study, we examined the effect of DIF-1 on c-Myc, a target gene product of the Wnt/β-catenin signaling pathway, mainly using HCT-116 colon cancer cells. DIF-1 strongly reduced the amount of c-Myc protein in time- and concentration-dependent manners and reduced c-Myc mRNA expression by inhibiting promoter activity through the TCF binding sites. The effect of DIF-1 on c-Myc was also confirmed using the human cervical cell line HeLa. Pretreatment with the proteasome inhibitor MG132 or glycogen synthase kinase-3β (GSK-3β) inhibitors (LiCl and SB216763) attenuated the effect of DIF-1, suggesting that DIF-1 induced c-Myc protein degradation through GSK-3β activation. Furthermore, we examined whether c-Myc was involved in the anti-proliferative effect of DIF-1 using c-Myc-overexpressing cells and found that c-Myc was associated with the anti-proliferative effect of this compound. These results suggest that DIF-1 inhibits c-Myc expression by inhibiting promoter activity and Inducing protein degradation via GSK-3β activation, resulting in the inhibition of cell proliferation. Since c-Myc seems to be profoundly involved in accelerated proliferation of various malignant tumors, DIF-1 may have a potential to develop into a novel anti-cancer agent.

Haruhisa Kikuchi - One of the best experts on this subject based on the ideXlab platform.

  • Dictyostelium Differentiation-Inducing Factor-1 Promotes Glucose Uptake, at Least in Part, via an AMPK-Dependent Pathway in Mouse 3T3-L1 Cells.
    International journal of molecular sciences, 2021
    Co-Authors: Yuzuru Kubohara, Yoshiteru Oshima, Yoshimi Homma, Hiroshi Shibata, Haruhisa Kikuchi
    Abstract:

    Differentiation-Inducing Factor-1 (DIF-1) is a chlorinated alkylphenone (a polyketide) found in the cellular slime mold Dictyostelium discoideum. DIF-1 and its derivative, DIF-1(3M) promote glucose consumption in vitro in mammalian cells and in vivo in diabetic rats; they are expected to be the leading antiobesity and antidiabetes compounds. In this study, we investigated the mechanisms underlying the actions of DIF-1 and DIF-1(3M). In isolated mouse liver mitochondria, these compounds at 2–20 mM promoted oxygen consumption in a dose-dependent manner, suggesting that they act as mitochondrial uncouplers, whereas CP-DIF-1 (another derivative of DIF-1) at 10–20 mM had no effect. In confluent mouse 3T3-L1 fibroblasts, DIF-1 and DIF-1(3M) but not CP-DIF-1 induced phosphorylation (and therefore activation) of AMP kinase (AMPK) and promoted glucose consumption and metabolism. The DIF-induced glucose consumption was reduced by compound C (an AMPK inhibitor) or AMPK knock down. These data suggest that DIF-1 and DIF-1(3M) promote glucose uptake, at least in part, via an AMPK-dependent pathway in 3T3-L1 cells, whereas cellular metabolome analysis revealed that DIF-1 and DIF-1(3M) may act differently at least in part.

  • Differentiation-Inducing Factor-1 prevents hepatic stellate cell activation through inhibiting GSK3β inactivation
    Biochemical and biophysical research communications, 2019
    Co-Authors: Shohei Furukawa, Momoka Yamaguchi, Akira Ooka, Haruhisa Kikuchi, Tomohisa Ishikawa, Shin-ya Saito
    Abstract:

    Differentiation-Inducing Factor-1 (DIF-1), a morphogen produced by the cellular slime mold Dictyostelium discoideum, is a natural product that has attracted considerable attention for its antitumor properties. Here, we report a novel inhibitory effect of DIF-1 on the activation of hepatic stellate cells (HSCs) responsible for liver fibrosis. DIF-1 drastically inhibited transDifferentiation of quiescent HSCs into myofibroblastic activated HSCs in a concentration-dependent manner, thus conferring an antifibrotic effect against in the liver. Neither SQ22536, an adenylate cyclase inhibitor, nor ODQ, a guanylate cyclase inhibitor, showed any effect on the inhibition of HSC activation by DIF-1. In contrast, TWS119, a glycogen synthase kinase 3β (GSK3β) inhibitor, attenuated the inhibitory effect of DIF-1. Moreover, the level of inactive GSK3β (phosphorylated at Ser9) was significantly reduced by DIF-1. DIF-1 also inhibited nuclear translocation of β-catenin and reduced the level of non-phospho (active) β-catenin. These results suggest that DIF-1 inhibits HSC activation by disrupting the Wnt/β-catenin signaling pathway through dephosphorylation of GSK3β. We propose that DIF-1 is a possible candidate as a therapeutic agent for preventing liver fibrosis.

  • Halogen-Substituted Derivatives of Dictyostelium Differentiation-Inducing Factor-1 Suppress Serum-Induced Cell Migration of Human Breast Cancer MDA-MB-231 Cells in Vitro.
    Biomolecules, 2019
    Co-Authors: Kyoko Totsuka, Katsunori Takahashi, Haruhisa Kikuchi, Yoshiteru Oshima, Yuka Makioka, Kyoichi Iizumi, Yuzuru Kubohara
    Abstract:

    Triple-negative breast cancer (TNBC) is highly proliferative and metastatic, and because it lacks three major molecular targets for chemotherapy (estrogen receptor, progesterone receptor, and human epidermal receptor 2), it is extremely refractory. Differentiation-Inducing Factor 1 (DIF-1) and DIF-3, which are chlorinated alkylphenones, are lead anticancer compounds found in the cellular slime mold Dictyostelium discoideum. Here, we examined the in vitro effects of DIF-1, DIF-3, and 25 DIF derivatives on cell proliferation and serum-induced cell migration in human MDA-MB-231 cells, a model TNBC cell line. We found that Br-DIF-1, a chlorine-to-bromine-substituted derivative of DIF-1, strongly suppressed cell migration (IC50, 3.8 M) with negligible effects on cell proliferation (IC50, >20 M). We then synthesized 18 derivatives of Br-DIF-1 and examined the in vitro effects of these derivatives on cell proliferation and serum-induced cell migration in MDA-MB-231 cells. Among the derivatives, Br-DIF-1(+1), Br-DIF-1(+2), and Br-DIF-3(+2) exhibited strong anti-cell migration activities with IC50 values of 1.5, 1.0, and 3.1 M, respectively, without affecting cell proliferation (IC50, >20 M). These results suggest that these Br-DIF derivatives are good lead compounds for the development of anti-metastatic drugs against TNBC.

  • Biological Activities of Novel Derivatives of Differentiation-Inducing Factor 3 from Dictyostelium discoideum.
    Biological & pharmaceutical bulletin, 2017
    Co-Authors: Katsunori Takahashi, Haruhisa Kikuchi, Yoshiteru Oshima, Van Hai Nguyen, Hirotaka Ishigaki, Junko Nakajima-shimada, Yuzuru Kubohara
    Abstract:

    Differentiation-Inducing Factor-3 (DIF-3; 1-(3-chloro-2,6-dihydroxy-4-methoxyphenyl)hexan-1-one), which is found in the cellular slime mold Dictyostelium discoideum, is a potential candidate compound for the development of new medicines; DIF-3 and its derivatives possess several beneficial biological activities, including anti-tumor, anti-Trypanosoma cruzi, and immunoregulatory effects. To assess the relationship between the biological activities of DIF-3 and its chemical structure, particularly in regard to its alkoxy group and the length of the alkyl chains at the acyl group, we synthesized two derivatives of DIF-3, 1-(3-chloro-2,6-dihydroxy-4-methoxyphenyl)octan-1-one (DIF-3(+3)) and 1-(3-chloro-2,6-dihydroxy-4-butoxyphenyl)-hexan-1-one (Hex-DIF-3), and investigated their biological activities in vitro. At micro-molar levels, DIF-3(+3) and Hex-DIF-3 exhibited strong anti-proliferative effects in tumor cell cultures, but their anti-T. cruzi activities at 1 µM in vitro were not as strong as those of other known DIF derivatives. In addition, Hex-DIF-3 at 5 µM significantly suppressed mitogen-induced interleukin-2 production in vitro in Jurkat T cells. These results suggest that DIF-3(+3) and Hex-DIF-3 are promising leads for the development of anti-cancer and immunosuppressive agents.

  • Evidence that Differentiation-Inducing Factor-1 controls chemotaxis and cell Differentiation, at least in part, via mitochondria in D. discoideum
    The Company of Biologists, 2017
    Co-Authors: Yuzuru Kubohara, Haruhisa Kikuchi, Hidekazu Kuwayama, Van Hai Nguyen, Yoshiteru Oshima
    Abstract:

    Differentiation-Inducing Factor-1 [1-(3,5-dichloro-2,6-dihydroxy-4-methoxyphenyl)hexan-1-one (DIF-1)] is an important regulator of cell Differentiation and chemotaxis in the development of the cellular slime mold Dictyostelium discoideum. However, the entire signaling pathways downstream of DIF-1 remain to be elucidated. To characterize DIF-1 and its potential receptor(s), we synthesized two fluorescent derivatives of DIF-1, boron-dipyrromethene (BODIPY)-conjugated DIF-1 (DIF-1-BODIPY) and nitrobenzoxadiazole (NBD)-conjugated DIF-1 (DIF-1-NBD), and investigated their biological activities and cellular localization. DIF-1-BODIPY (5 µM) and DIF-1 (2 nM) induced stalk cell Differentiation in the DIF-deficient strain HM44 in the presence of cyclic adenosine monosphosphate (cAMP), whereas DIF-1-NBD (5 µM) hardly induced stalk cell Differentiation under the same conditions. Microscopic analyses revealed that the biologically active derivative, DIF-1-BODIPY, was incorporated by stalk cells at late stages of Differentiation and was localized to mitochondria. The mitochondrial uncouplers carbonyl cyanide m-chlorophenylhydrazone (CCCP), at 25–50 nM, and dinitrophenol (DNP), at 2.5–5 µM, induced partial stalk cell Differentiation in HM44 in the presence of cAMP. DIF-1-BODIPY (1–2 µM) and DIF-1 (10 nM), as well as CCCP and DNP, suppressed chemotaxis in the wild-type strain Ax2 in shallow cAMP gradients. These results suggest that DIF-1-BODIPY and DIF-1 induce stalk cell Differentiation and modulate chemotaxis, at least in part, by disturbing mitochondrial activity

Yoshiteru Oshima - One of the best experts on this subject based on the ideXlab platform.

  • Dictyostelium Differentiation-Inducing Factor-1 Promotes Glucose Uptake, at Least in Part, via an AMPK-Dependent Pathway in Mouse 3T3-L1 Cells.
    International journal of molecular sciences, 2021
    Co-Authors: Yuzuru Kubohara, Yoshiteru Oshima, Yoshimi Homma, Hiroshi Shibata, Haruhisa Kikuchi
    Abstract:

    Differentiation-Inducing Factor-1 (DIF-1) is a chlorinated alkylphenone (a polyketide) found in the cellular slime mold Dictyostelium discoideum. DIF-1 and its derivative, DIF-1(3M) promote glucose consumption in vitro in mammalian cells and in vivo in diabetic rats; they are expected to be the leading antiobesity and antidiabetes compounds. In this study, we investigated the mechanisms underlying the actions of DIF-1 and DIF-1(3M). In isolated mouse liver mitochondria, these compounds at 2–20 mM promoted oxygen consumption in a dose-dependent manner, suggesting that they act as mitochondrial uncouplers, whereas CP-DIF-1 (another derivative of DIF-1) at 10–20 mM had no effect. In confluent mouse 3T3-L1 fibroblasts, DIF-1 and DIF-1(3M) but not CP-DIF-1 induced phosphorylation (and therefore activation) of AMP kinase (AMPK) and promoted glucose consumption and metabolism. The DIF-induced glucose consumption was reduced by compound C (an AMPK inhibitor) or AMPK knock down. These data suggest that DIF-1 and DIF-1(3M) promote glucose uptake, at least in part, via an AMPK-dependent pathway in 3T3-L1 cells, whereas cellular metabolome analysis revealed that DIF-1 and DIF-1(3M) may act differently at least in part.

  • Halogen-Substituted Derivatives of Dictyostelium Differentiation-Inducing Factor-1 Suppress Serum-Induced Cell Migration of Human Breast Cancer MDA-MB-231 Cells in Vitro.
    Biomolecules, 2019
    Co-Authors: Kyoko Totsuka, Katsunori Takahashi, Haruhisa Kikuchi, Yoshiteru Oshima, Yuka Makioka, Kyoichi Iizumi, Yuzuru Kubohara
    Abstract:

    Triple-negative breast cancer (TNBC) is highly proliferative and metastatic, and because it lacks three major molecular targets for chemotherapy (estrogen receptor, progesterone receptor, and human epidermal receptor 2), it is extremely refractory. Differentiation-Inducing Factor 1 (DIF-1) and DIF-3, which are chlorinated alkylphenones, are lead anticancer compounds found in the cellular slime mold Dictyostelium discoideum. Here, we examined the in vitro effects of DIF-1, DIF-3, and 25 DIF derivatives on cell proliferation and serum-induced cell migration in human MDA-MB-231 cells, a model TNBC cell line. We found that Br-DIF-1, a chlorine-to-bromine-substituted derivative of DIF-1, strongly suppressed cell migration (IC50, 3.8 M) with negligible effects on cell proliferation (IC50, >20 M). We then synthesized 18 derivatives of Br-DIF-1 and examined the in vitro effects of these derivatives on cell proliferation and serum-induced cell migration in MDA-MB-231 cells. Among the derivatives, Br-DIF-1(+1), Br-DIF-1(+2), and Br-DIF-3(+2) exhibited strong anti-cell migration activities with IC50 values of 1.5, 1.0, and 3.1 M, respectively, without affecting cell proliferation (IC50, >20 M). These results suggest that these Br-DIF derivatives are good lead compounds for the development of anti-metastatic drugs against TNBC.

  • Biological Activities of Novel Derivatives of Differentiation-Inducing Factor 3 from Dictyostelium discoideum.
    Biological & pharmaceutical bulletin, 2017
    Co-Authors: Katsunori Takahashi, Haruhisa Kikuchi, Yoshiteru Oshima, Van Hai Nguyen, Hirotaka Ishigaki, Junko Nakajima-shimada, Yuzuru Kubohara
    Abstract:

    Differentiation-Inducing Factor-3 (DIF-3; 1-(3-chloro-2,6-dihydroxy-4-methoxyphenyl)hexan-1-one), which is found in the cellular slime mold Dictyostelium discoideum, is a potential candidate compound for the development of new medicines; DIF-3 and its derivatives possess several beneficial biological activities, including anti-tumor, anti-Trypanosoma cruzi, and immunoregulatory effects. To assess the relationship between the biological activities of DIF-3 and its chemical structure, particularly in regard to its alkoxy group and the length of the alkyl chains at the acyl group, we synthesized two derivatives of DIF-3, 1-(3-chloro-2,6-dihydroxy-4-methoxyphenyl)octan-1-one (DIF-3(+3)) and 1-(3-chloro-2,6-dihydroxy-4-butoxyphenyl)-hexan-1-one (Hex-DIF-3), and investigated their biological activities in vitro. At micro-molar levels, DIF-3(+3) and Hex-DIF-3 exhibited strong anti-proliferative effects in tumor cell cultures, but their anti-T. cruzi activities at 1 µM in vitro were not as strong as those of other known DIF derivatives. In addition, Hex-DIF-3 at 5 µM significantly suppressed mitogen-induced interleukin-2 production in vitro in Jurkat T cells. These results suggest that DIF-3(+3) and Hex-DIF-3 are promising leads for the development of anti-cancer and immunosuppressive agents.

  • Evidence that Differentiation-Inducing Factor-1 controls chemotaxis and cell Differentiation, at least in part, via mitochondria in D. discoideum
    The Company of Biologists, 2017
    Co-Authors: Yuzuru Kubohara, Haruhisa Kikuchi, Hidekazu Kuwayama, Van Hai Nguyen, Yoshiteru Oshima
    Abstract:

    Differentiation-Inducing Factor-1 [1-(3,5-dichloro-2,6-dihydroxy-4-methoxyphenyl)hexan-1-one (DIF-1)] is an important regulator of cell Differentiation and chemotaxis in the development of the cellular slime mold Dictyostelium discoideum. However, the entire signaling pathways downstream of DIF-1 remain to be elucidated. To characterize DIF-1 and its potential receptor(s), we synthesized two fluorescent derivatives of DIF-1, boron-dipyrromethene (BODIPY)-conjugated DIF-1 (DIF-1-BODIPY) and nitrobenzoxadiazole (NBD)-conjugated DIF-1 (DIF-1-NBD), and investigated their biological activities and cellular localization. DIF-1-BODIPY (5 µM) and DIF-1 (2 nM) induced stalk cell Differentiation in the DIF-deficient strain HM44 in the presence of cyclic adenosine monosphosphate (cAMP), whereas DIF-1-NBD (5 µM) hardly induced stalk cell Differentiation under the same conditions. Microscopic analyses revealed that the biologically active derivative, DIF-1-BODIPY, was incorporated by stalk cells at late stages of Differentiation and was localized to mitochondria. The mitochondrial uncouplers carbonyl cyanide m-chlorophenylhydrazone (CCCP), at 25–50 nM, and dinitrophenol (DNP), at 2.5–5 µM, induced partial stalk cell Differentiation in HM44 in the presence of cAMP. DIF-1-BODIPY (1–2 µM) and DIF-1 (10 nM), as well as CCCP and DNP, suppressed chemotaxis in the wild-type strain Ax2 in shallow cAMP gradients. These results suggest that DIF-1-BODIPY and DIF-1 induce stalk cell Differentiation and modulate chemotaxis, at least in part, by disturbing mitochondrial activity

  • Oral administration of Dictyostelium Differentiation-Inducing Factor 1 lowers blood glucose levels in streptozotocin-induced diabetic rats.
    Life sciences, 2016
    Co-Authors: Ritsuko Kawaharada, Katsunori Takahashi, Haruhisa Kikuchi, Yoshiteru Oshima, Akio Nakamura, Yuzuru Kubohara
    Abstract:

    Abstract Aims Differentiation-Inducing Factor 1 (DIF-1), originally discovered in the cellular slime mold Dictyostelium discoideum , and its derivatives possess pharmacological activities, such as the promotion of glucose uptake in non-transformed mammalian cells in vitro . Accordingly, DIFs are considered promising lead candidates for novel anti-diabetic drugs. The aim of this study was to assess the anti-diabetic and toxic effects of DIF-1 in mouse 3T3-L1 fibroblast cells in vitro and in diabetic rats in vivo . Main methods We investigated the in vitro effects of DIF-1 and DIF-1(3M), a derivative of DIF-1, on glucose metabolism in 3T3-L1 cells by using capillary electrophoresis time-of-flight mass spectrometry (CE-TOF-MS). We also examined the effects of DIF-1 on blood glucose levels in streptozotocin (STZ)-induced rats. Key findings . CE-TOF-MS revealed that 20 μM DIF-1 and 20 μM DIF-1(3M) promoted glucose uptake and metabolism in 3T3-L1 cells. Oral administration of DIF-1 (30 mg/kg) significantly lowered basal blood glucose levels in STZ-treated rats and promoted a decrease in blood glucose levels after oral glucose loading (2.5 g/kg) in the rats. In addition, daily oral administration of DIF-1 (30 mg/kg/day) for 1 wk significantly lowered the blood glucose levels in STZ-treated rats but did not affect their body weight and caused only minor alterations in the levels of other blood analytes. Significance These results indicate that DIF-1 may be a good lead compound for the development of anti-diabetic drugs.