論文 - 井本　正哉

Identification of protein kinase C isozymes involved in the anti-proliferative and pro-apoptotic activities of 10-Methyl-aplog-1, a simplified analog of debromoaplysiatoxin, in several cancer cell lines

Hanaki Y., Shikata Y., Kikumori M., Hotta N., Imoto M., Irie K.

Biochemical and Biophysical Research Communications （Biochemical and Biophysical Research Communications）  495 （ 1 ） 438 - 445 2018年01月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  0006291X

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© 2017 Elsevier Inc. 10-Me-aplog-1 is a simplified analog of the tumor-promoting compound debromoaplysiatoxin (DAT) and a unique protein kinase C (PKC) activator with limited tumor-promoting and pro-inflammatory activities. 10-Me-aplog-1 inhibits the growth of several cancer cell lines, but the inhibitory mechanism involving PKC isozymes remains unclear. We quantified the amount of PKC isozymes in nine human cancer cell lines that differ in 10-Me-aplog-1 sensitivity. PKCα and δ were the predominant isozymes expressed in all cell lines, but there was no significant correlation between expression levels and anti-proliferative activity. Knocking down PKCα, and/or PKCδ in the three aplog-sensitive cell lines indicated their involvement in the anti-proliferative and pro-apoptotic activities of 10-Me-aplog-1. This finding suggests that PKCα and/or PKCδ activation could be effective for treating certain cancers. Since the mechanism underlying 10-Me-aplog-1's anti-proliferative activities resembles that of DAT, 10-Me-aplog-1 may be regarded as a special key derived from pleiotropic DAT as a bunch of keys.

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Professor Hamao Umezawa opened up a new road for the development of molecularly targeted therapeutic drugs for cancers

Imoto M.

Journal of Antibiotics （Journal of Antibiotics）  71 （ 1 ） 37 - 38 2018年01月

研究論文（学術雑誌）, 単著, 査読有り,  ISSN  00218820

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© 2018 Japan Antibiotics Research Association All rights reserved. This issue is dedicated to Prof Hamao Umezawa in appreciation of his great contributions to pioneering research on antibiotics targeting oncogenes.

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Drug discovery inspired by chemical biology

Osada Hiroyuki, Imoto Masaya

CANCER SCIENCE 109   149 - 149 2018年01月

研究論文（学術雑誌）, 査読有り,  ISSN  1349-7006

Synthetic lethal interaction of VCP inhibitor with PKA inhibitor

Tashiro Etsu, Shikata Yuki, Katoh Hiroto, Ishikawa Shumpei, Imoto Masaya

CANCER SCIENCE 109   372 - 372 2018年01月

研究論文（学術雑誌）, 査読有り,  ISSN  1349-7006

Synthetic lethal killing of beta-catenin mutant cancer cells by small molecules

Imoto Masaya

CANCER SCIENCE 109   150 - 150 2018年01月

研究論文（学術雑誌）, 査読有り,  ISSN  1349-7006

Screening of the compounds that modulate cellular bilirubin level in hepatocellular carcinoma HepG2 cells

Kataura Tetsushi, Imoto Masaya

MOLECULAR CANCER THERAPEUTICS 17 （ 1 ）  2018年01月

ISSN  1535-7163

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Rupture of a Calyceal Diverticulum Secondary to Ureteroscopy: A Rare Complication.

Yamasaki T, Yoshioka T, Imoto M, Aoki H, Fujio K, Uehara S, Otsuki H

Case reports in urology 2018   9285671 - 9285671 2018年

研究論文（学術雑誌）, 査読有り,  ISSN  2090-696X

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We present a case of a 45-year-old female who experienced rupture of a right calyceal diverticulum caused by ureteroscopy. Fifteen hours after the operation, she had severe right flank pain and a high fever (38.9°C). Computed tomography revealed perinephric extravasation of urine and bleeding inside the diverticulum. We diagnosed rupture of a calyceal diverticulum; therefore, we continued antibiotic administration and pain relief medication. She became afebrile on postoperative day 4 and was discharged from the hospital on postoperative day 7. Owing to renal cortex thinning in the diverticula, ureteroscopy is associated with a risk of rupture of calyceal diverticula.

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天然物スクリーニングとケミカルバイオロジーへの展開

井本 正哉

化学と生物 （公益社団法人 日本農芸化学会）  56 （ 3 ） 203 - 209 2018年

研究論文（学術雑誌）, 査読有り,  ISSN  0453-073X

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<p>天然物創薬研究が衰退しつつある今日，このたびの遠藤先生のガードナー国際賞ご受賞は「天然物スクリーニングから創薬へ」を再認識させ，これが天然物創薬研究の再活性化につながることになることを期待する．天然物スクリーニングは創薬研究だけでなく，ケミカルバイオロジー研究を展開するうえでのバイオプローブの探索でも非常に有効な手段である．ここでは，話題提供として，われわれの「創薬に至らなかった天然物スクリーニングとケミカルバイオロジーへの展開」を紹介する．</p>

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「宝探し」と「謎解き」を楽しむ天然物ケミカルバイオロジー

井本 正哉

化学と生物 （公益社団法人 日本農芸化学会）  56 （ 5 ） 307 - 307 2018年

研究論文（学術雑誌）, 査読有り,  ISSN  0453-073X

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Apoptosis and autophagy

Tashiro E., Kitagawa M., Imoto M.

Bioprobes: Biochemical Tools for Investigating Cell Function: Second Edition （Bioprobes: Biochemical Tools for Investigating Cell Function: Second Edition）     75 - 113 2017年05月

研究論文（学術雑誌）, 査読有り,  ISSN  9784431565277

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© Springer Japan KK 2017. Apoptosis and autophagy are highly coordinated mechanisms to maintain cellular homeostasis against various intrinsic and/or extrinsic stresses in eukaryotic cells. Since the early 1990s, our knowledge of the molecular mechanisms and the physiological functions of apoptosis have increased substantially. Dysfunction of apoptosis leads to various diseases, including cancers and degenerative diseases. Therefore, small molecules that induce apoptosis or synthetic lethality with mutated genes have been examined for the development of cancer-specific apoptosis-inducing agents; conversely, small molecules that suppress apoptosis have been identified for protective agents against neuronal cell death. On the other hand, autophagy is an evolutionarily conserved pathway involved in the degradation of intracellular components and is critical for the maintenance of cellular homeostasis. The mechanisms and functions of autophagy have been revealed by genetic studies in yeast, which identified a series of autophagy-related genes. Many small molecules that have been discovered to induce or inhibit autophagy also provide insight into the mechanisms and functions of the autophagic process. In this chapter, we introduce several small molecules identified by synthetic lethality screening, apoptosis inhibitors, and autophagy modulators.

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Antarlides F-H, new members of the antarlide family produced by Streptomyces sp. BB47

Saito S., Fujimaki T., Panbangred W., Sawa R., Igarashi Y., Imoto M.

Journal of Antibiotics （Journal of Antibiotics）  70 （ 5 ） 595 - 600 2017年05月

研究論文（学術雑誌）, 査読有り,  ISSN  00218820

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© 2017 Japan Antibiotics Research Association All rights reserved. Castration-resistant prostate cancer (CRPC) is the most aggressive form of this disease. CRPC remains dependent on androgen receptor (AR) signaling. Therefore, a novel AR antagonist, enzalutamide, is used clinically for the treatment of men with metastatic CRPC. However, enzalutamide-resistant AR has appeared, and a new type of AR antagonist is desired. Previously, in the course of screening for a new type of AR antagonist, we isolated a series of compounds, designated antarlides A-E, that share a novel 22-membered-ring macrocyclic structure and are produced by Streptomyces sp. BB47. In the present study, we found that this strain also produces antarlides F-H as minor components. Antarlide F is a novel geometric isomer of known antarlides. On the other hand, antarlides G and H are new members of the antarlide family that have a 20-membered-ring macrocyclic structure. Antarlides G and H inhibited the binding of androgen to AR in vitro at concentrations similar to those observed with antarlides A-E. In addition, antarlide G inhibited the transcriptional activity of not only wild-type AR but also enzalutamide-resistant AR, suggesting that antarlides with either 22- or 20-membered rings may serve as potent third-generation AR antagonists capable of overcoming resistance to enzalutamide.

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Mitochondrial uncoupler exerts a synthetic lethal effect against β-catenin mutant tumor cells

Shikata Y., Kiga M., Futamura Y., Aono H., Inoue H., Kawada M., Osada H., Imoto M.

Cancer Science （Cancer Science）  108 （ 4 ） 772 - 784 2017年04月

研究論文（学術雑誌）, 査読有り,  ISSN  13479032

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© 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. The wingless/int-1 (Wnt) signal transduction pathway plays a central role in cell proliferation, survival, differentiation and apoptosis. When β-catenin: a component of the Wnt pathway, is mutated into an active form, cell growth signaling is hyperactive and drives oncogenesis. As β-catenin is mutated in a wide variety of tumors, including up to 10% of all sporadic colon carcinomas and 20% of hepatocellular carcinomas, it has been considered a promising target for therapeutic interventions. Therefore, we screened an in-house natural product library for compounds that exhibited synthetic lethality towards β-catenin mutations and isolated nonactin, an antibiotic mitochondrial uncoupler, as a hit compound. Nonactin, as well as other mitochondrial uncouplers, induced apoptosis selectively in β-catenin mutated tumor cells. Significant tumor regression was observed in the β-catenin mutant HCT 116 xenograft model, but not in the β-catenin wild type A375 xenograft model, in response to daily administration of nonactin in vivo. Furthermore, we found that expression of an active mutant form of β-catenin induced a decrease in the glycolysis rate. Taken together, our results demonstrate that tumor cells with mutated β-catenin depend on mitochondrial oxidative phosphorylation for survival. Therefore, they undergo apoptosis in response to mitochondrial dysfunction following the addition of mitochondrial uncouplers, such as nonactin. These results suggest that targeting mitochondria is a potential chemotherapeutic strategy for tumor cells that harbor β-catenin mutations.

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Protein kinase A inhibition facilitates the antitumor activity of xanthohumol, a valosin-containing protein inhibitor

Shikata Y., Yoshimaru T., Komatsu M., Katoh H., Sato R., Kanagaki S., Okazaki Y., Toyokuni S., Tashiro E., Ishikawa S., Katagiri T., Imoto M.

Cancer Science （Cancer Science）  108 （ 4 ） 785 - 794 2017年04月

研究論文（学術雑誌）, 査読有り,  ISSN  13479032

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© 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. Xanthohumol (XN), a simple prenylated chalcone, can be isolated from hops and has the potential to be a cancer chemopreventive agent against several human tumor cell lines. We previously identified valosin-containing protein (VCP) as a target of XN; VCP can also play crucial roles in cancer progression and prognosis. Therefore, we investigated the molecular mechanisms governing the contribution of VCP to the antitumor activity of XN. Several human tumor cell lines were treated with XN to investigate which human tumor cell lines are sensitive to XN. Several cell lines exhibited high sensitivity to XN both in vitro and in vivo. shRNA screening and bioinformatics analysis identified that the inhibition of the adenylate cyclase (AC) pathway synergistically facilitated apoptosis induced by VCP inhibition. These results suggest that there is crosstalk between the AC pathway and VCP function, and targeting both VCP and the AC pathway is a potential chemotherapeutic strategy for a subset of tumor cells.

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Metacycloprodigiosin induced cell death selectively in β-catenin-mutated tumor cells

Ikeda H., Shikata Y., Watanapokasin R., Tashiro E., Imoto M.

Journal of Antibiotics （Journal of Antibiotics）  70 （ 1 ） 109 - 112 2017年01月

研究論文（学術雑誌）, 査読有り,  ISSN  00218820

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Involvement of the MEK/ERK pathway in EGF-induced E-cadherin down-regulation

Tashiro E., Henmi S., Odake H., Ino S., Imoto M.

Biochemical and Biophysical Research Communications （Biochemical and Biophysical Research Communications）  477 （ 4 ） 801 - 806 2016年09月

研究論文（学術雑誌）, 査読有り,  ISSN  0006291X

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© 2016 Elsevier Inc. E-cadherin is a major component of the epithelial adherens junction. However, the regulatory mechanism of E-cadherin expression is still poorly understood. In this study, we found that EGF decreased E-cadherin expression at both mRNA and protein levels in colorectal carcinoma LoVo cells. Since E-cadherin down-regulation is a well-known hallmark of the EMT (Epithelial-Mesenchymal Transition), we investigated whether EGF induced E-cadherin down-regulation during the EMT. EGF was unable to affect the expression of mesenchymal markers (such as N-cadherin, vimentin or fibronectin) or EMT-regulating transcription factors (such as SNAIL, SLUG, ZEB1, ZEB2 or TWIST), suggesting that EGF induced E-cadherin down-regulation via an EMT-independent mechanism. On the other hand, the MEK inhibitor U0126 was found to suppress EGF-induced E-cadherin down-regulation at the transcriptional level, suggesting that the MEK/ERK pathway is involved in EGF-induced E-cadherin down-regulation. Moreover, we also found that EGF disrupted cell-cell contact, stimulated cells to form an elongated shape with filamentous protrusions, and induced cell migration in LoVo cells. These effects were suppressed by U0126. Therefore, EGF is suggested to induce E-cadherin down-regulation at the transcriptional level through the MEK/ERK pathway, which might result in, at least in part, the induction of cellular morphological changes and cell migration in LoVo cells.

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Antiproliferative and apoptosis induction of α-mangostin in T47D breast cancer cells

Kritsanawong S., Innajak S., Imoto M., Watanapokasin R.

International Journal of Oncology （International Journal of Oncology）  48 （ 5 ） 2155 - 2165 2016年05月

研究論文（学術雑誌）, 査読有り,  ISSN  10196439

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α-Mangostin extracted from mangosteen, Garcinia mangostana Linn. is known as 'queen of fruits'. The anticancer activity of α-mangostin through apoptosis induction and related signaling pathways in human breast cancer T47D cells was investigated. Human epidermal growth factor receptor 2 (HER2) and mitogen-activated protein kinase (MAPK) signaling have been shown to play important roles in apoptosis. The results showed that α-mangostin induced cell proliferation inhibition, DNA fragmentation, nuclear condensation, increased cleaved caspase-3 and cleaved caspase-9, but decreased Bcl-2 and Mcl-1 expression. Mitochondrial dysfunction and cytochrome c release were also detected. In addition, phosphorylation of ERα, HER2, PI3K, Akt and ERK1/2 were downregulated whereas p-JNK1/2 and p-p38 were upregulated. These results indicated that α-mangostin induced apoptosis associated with HER2/PI3K/Akt and MAPK signaling pathways suggesting that α-mangostin may be used as food supplement or a potential therapeutic compound for breast cancer.

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Ulbactins F and G, Polycyclic Thiazoline Derivatives with Tumor Cell Migration Inhibitory Activity from Brevibacillus sp.

Igarashi Y., Asano D., Sawamura M., In Y., Ishida T., Imoto M.

Organic Letters （Organic Letters）  18 （ 7 ） 1658 - 1661 2016年04月

研究論文（学術雑誌）, 査読有り,  ISSN  15237060

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© 2016 American Chemical Society. Two new structurally unique compounds bearing a nitrogen- and sulfur-containing tricyclic ring system, ulbactin F (1) and its diastereomeric isomer ulbactin G (2), were isolated from the culture extract of a sponge-derived Brevibacillus sp. The structures and absolute configurations of 1 and 2 were determined by NMR analysis and X-ray crystallographic analysis. These compounds inhibit the migration of tumor cells in the submicromolar to micromolar range.

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Chemistry and biology of the compounds that modulate cell migration

Tashiro E., Imoto M.

Journal of Industrial Microbiology and Biotechnology （Journal of Industrial Microbiology and Biotechnology）  43 （ 2-3 ） 213 - 219 2016年03月

研究論文（学術雑誌）, 査読有り,  ISSN  13675435

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© 2015, Society for Industrial Microbiology and Biotechnology. Cell migration is a fundamental step for embryonic development, wound repair, immune responses, and tumor cell invasion and metastasis. Extensive studies have attempted to reveal the molecular mechanisms behind cell migration; however, they remain largely unclear. Bioactive compounds that modulate cell migration show promise as not only extremely powerful tools for studying the mechanisms behind cell migration but also as drug seeds for chemotherapy against tumor metastasis. Therefore, we have screened cell migration inhibitors and analyzed their mechanisms for the inhibition of cell migration. In this mini-review, we introduce our chemical and biological studies of three cell migration inhibitors: moverastin, UTKO1, and BU-4664L.

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Antarlides: A New Type of Androgen Receptor (AR) Antagonist that Overcomes Resistance to AR-Targeted Therapy

Saito S., Fujimaki T., Panbangred W., Igarashi Y., Imoto M.

Angewandte Chemie - International Edition （Angewandte Chemie - International Edition）  55 （ 8 ） 2728 - 2732 2016年02月

研究論文（学術雑誌）, 査読有り,  ISSN  14337851

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© 2016 Wiley-VCH Verlag GmbH & Co. KGaA. Prostate cancer is treated with androgen receptor (AR) antagonists but most patients experience disease progression after long-term treatment with these compounds. Therefore, new AR antagonists are required for patient follow-up treatment. In the course of screening for a new AR antagonist, we isolated the novel compounds antarlides A-E (1-5) from Streptomyces sp. BB47. Antarlides are mutually isomeric with respect to the double bond and have a 22-membered-ring macrocyclic structure. The full stereostructure of 1 was established by chemical modifications, including methanolysis, the Trost method, acetonide formation, and the PGME method. 1-5 inhibited the binding of androgen to ARs in vitro. In addition, 2 inhibited the transcriptional activity of not only wild-type AR but also mutant ARs, which are seen in patients with acquired resistance to clinically used AR antagonists. Therefore, antarlides are a potent new generation of AR antagonists that overcome resistance.

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Biological activities of unique isoflavones prepared from Apios americana Medik

Kaneta H., Koda M., Saito S., Imoto M., Kawada M., Yamazaki Y., Momose I., Shindo K.

Bioscience, Biotechnology and Biochemistry （Bioscience, Biotechnology and Biochemistry）  80 （ 4 ） 774 - 778 2016年

研究論文（学術雑誌）, 査読有り,  ISSN  09168451

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© 2016 Japan Society for Bioscience, Biotechnology, and Agrochemistry. Four unique isoflavone aglycones (barpisoflavone A (1), 2′-hydroxygenistein (2), 5-methylgenistein (3), and gerontoisoflavone A (4)) whose structures were related to genistein were prepared from the tuber of Apios americana Medik. We examined the estrogen receptor and androgen receptor binding activities, estrogen agonistic activities, antioxidant activities, and α-glucosidase inhibitory activities of 1.4. The results obtained showed that 2 possessed potent and 1, 3, and 4 possessed moderate estrogen partial agonistic activities, 1 and 2 possessed moderate antioxidant activities, and 2 and 3 possessed moderate α-glucosidase inhibitory activities.

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