Faculty Profiles - TOYOKUNI Shinya

Papers - TOYOKUNI Shinya

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Phlebotomy attenuates the growth of malignant mesothelioma on rat model

Ohara Yuuki, Toyokuni Shinya

CANCER SCIENCE Vol. 109 page： 781 - 781 2018.1

Molecular mechanisms in oxidative stress-induced carcinogenesis

Toyokuni Shinya

CANCER SCIENCE Vol. 109 page： 163 - 163 2018.1

Ferric nitrilotriacetate induced renal tumorigenesis in MUTYH deficient mice

Akatsuka Shinya, Li Guang-Hua, Sakumi Kunihiko, Nakabeppu Yusaku, Futakuchi Mitsuru, Suzuki Hiromu, Toyokuni Shinya

CANCER SCIENCE Vol. 109 page： 167 - 167 2018.1

Ferric nitrilotriacetate induced renal tumorigenesis in MUTYH deficient mice International journal

Akatsuka Shinya, Li Guang-Hua, Sakumi Kunihiko, Nakabeppu Yusaku, Futakuchi Mitsuru, Suzuki Hiromu, Toyokuni Shinya

CANCER SCIENCE Vol. 109 page： 167-167 2018.1

Molecular mechanisms in oxidative stress-induced carcinogenesis International journal

Toyokuni Shinya

CANCER SCIENCE Vol. 109 page： 163-163 2018.1

Phlebotomy attenuates the growth of malignant mesothelioma on rat model International journal

Ohara Yuuki, Toyokuni Shinya

CANCER SCIENCE Vol. 109 page： 781-781 2018.1

Glioblastoma Cell Lines Display Different Sensitivities to Plasma-Activated Medium International journal

Tanaka Hiromasa, Mizuno Masaaki, Ishikawa Kenji, Takeda Keigo, Hashizume Hiroshi, Nakamura Kae, Utsumi Fumi, Kajiyama Hiroaki, Okazaki Yasumasa, Toyokuni Shinya, Akiyama Shinichi, Maruyama Shoichi, Kikkawa Fumitaka, Hori Masaru

IEEE TRANSACTIONS ON RADIATION AND PLASMA MEDICAL SCIENCES Vol. 2 ( 2 ) page： 99 - 102 2018

Language：English Publishing type：Research paper (scientific journal) Publisher：IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC

Plasma-activated medium (PAM) is a novel chemotherapy that induces reactive oxygen species (ROS) and cell death in a wide range of cancer cell types, suggesting that PAM may be a promising therapeutic option for cancer treatment. However, dose response experiments suggest that PAM sensitivity is cell line specific. We examined the sensitivities of three glioblastoma cell lines to PAM, and found a wide variation in cell killing that was linked to differences in PAM induced ROS and apoptosis. These results indicate that the PAM sensitivity of glioblastoma cells, and potentially cancer cells more generally, is heterogeneous and likely to be dependent on the regulation of apoptosis and antioxidant pathways in target cells.

DOI： 10.1109/trpms.2017.2721973

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State of the art in medical applications using non-thermal atmospheric pressure plasma Reviewed International journal

Hiromasa Tanaka, Kenji Ishikawa, Masaaki Mizuno, Shinya Toyokuni, Hiroaki Kajiyama, Fumitaka Kikkawa, Hans-Robert Metelmann, Masaru Hori

Plasma Physics, Association of Asia Pacific Physical Societies 2017 Vol. 1 ( 1 ) 2017.12

Phlebotomy as a preventive measure for crocidolite-induced mesothelioma in male rats. Reviewed International journal

Ohara Y, Chew SH, Shibata T, Okazaki Y, Yamashita K, Toyokuni S

Cancer Science 2017.11

Fenton reaction-induced renal carcinogenesis in Mutyh-deficient mice exhibits less chromosomal aberrations than the rat model. Reviewed

Li GH, Akatsuka S, Chew SH, Jiang L, Nishiyama T, Sakamoto A, Takahashi T, Futakuchi M, Suzuki H, Sakumi K, Nakabeppu Y, Toyokuni S.

Pathology International Vol. 67 ( 11 ) page： 564-574 2017.11

Role of catalytic iron and oxidative stress in nitrofen-induced congenital diaphragmatic hernia and its amelioration by Saireito (TJ-114) Reviewed International journal

Shima Hirako, Hiroyuki Tsuda, Fumiya Ito, Yasumasa Okazaki, Tasuku Hirayama, Hideko Nagasawa, Tomoko Nakano, Kenji Imai, Tomomi Kotani, Fumitaka Kikkawa, Shinya Toyokuni

JOURNAL OF CLINICAL BIOCHEMISTRY AND NUTRITION Vol. 61 ( 3 ) page： 176 - 182 2017.11

Language：English Publishing type：Research paper (scientific journal) Publisher：JOURNAL CLINICAL BIOCHEMISTRY & NUTRITION

Congenital diaphragmatic hernia (CDH) is a life-threatening neonatal disease that leads to lung hypoplasia and pulmonary hypertension. We recently found that maternal prenatal administration of Saireito (TJ-114) ameliorates fetal CDH in a nitrofen-induced rat model. Here, we studied the role of iron and oxidative stress in neonates of this model and in lung fibroblasts IMR90-SV in association with nitrofen and Saireito. We observed increased immunostaining of 8-hydroxy-2'-deoxyguanosine in the lungs of neonates with CDH, which was ameliorated by maternal Saireito intake. Pulmonary transferrin receptor expression was significantly decreased in both CDH and CDH after Saireito in comparison to normal controls, indicating functional lung immaturity, whereas catalytic Fe(II) and pulmonary DMT1/ferroportin expression remained constant among the three groups. Saireito revealed a dose-dependent scavenging capacity with electron spin resonance spin trapping in vitro against hydroxyl radicals but not against superoxide. Finally, nitrofen revealed dose-dependent cytotoxicity to IMR90-SV cells, accompanied by an increase in oxidative stress, as seen by 5(6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate and catalytic Fe(II). Saireito ameliorated all of these in IMR90-SV cells. In conclusion, catalytic Fe(II)-dependent oxidative stress by nitrofen may be the pathogenic cause of CDH, and the antioxidative activity of Saireito is at least partially responsible for improving nitrofen-induced CDH.

DOI： 10.3164/jcbn.17-17

Fenton reaction-induced renal carcinogenesis in Mutyh-deficient mice exhibits less chromosomal aberrations than the rat model International journal

Guang Hua Li, Shinya Akatsuka, Shan Hwu Chew, Li Jiang, Takahiro Nishiyama, Akihiko Sakamoto, Takashi Takahashi, Mitsuru Futakuchi, Hiromu Suzuki, Kunihiko Sakumi, Yusaku Nakabeppu, Shinya Toyokuni

PATHOLOGY INTERNATIONAL Vol. 67 ( 11 ) page： 564 - 574 2017.11

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY

Oxidative stress including iron excess has been associated with carcinogenesis. The level of 8-oxoguanine, a major oxidatively modified base in DNA, is maintained very low by three distinct enzymes, encoded by OGG1, MUTYH and MTH1. Germline biallelic inactivation of MUTYH represents a familial cancer syndrome called MUTYH-associated polyposis. Here, we used Mutyh-deficient mice to evaluate renal carcinogenesis induced by ferric nitrilotriacetate (Fe-NTA). Although the C57BL/6 background is cancer-resistant, a repeated intraperitoneal administration of Fe-NTA induced a high incidence of renal cell carcinoma (RCC; 26.7%) in Mutyh-deficient mice in comparison to wild-type mice (7.1%). Fe-NTA treatment also induced renal malignant lymphoma, which did not occur without the Fe-NTA treatment in both the genotypes. Renal tumor-free survival after Fe-NTA treatment was marginally different (P=0.157) between the two genotypes. Array-based comparative genome hybridization analyses revealed, in RCC, the loss of heterozygosity in chromosomes 4 and 12 without p16(INKA) inactivation; these results were confirmed by a methylation analysis and showed no significant difference between the genotypes. Lymphomas showed a preference for genomic amplifications. Dlk1 inactivation by promoter methylation may be involved in carcinogenesis in both tumors. Fe-NTA-induced murine RCCs revealed significantly less genomic aberrations than those in rats, demonstrating a marked species difference.

DOI： 10.1111/pin.12598

Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease. International journal

Brent R Stockwell, José Pedro Friedmann Angeli, Hülya Bayir, Ashley I Bush, Marcus Conrad, Scott J Dixon, Simone Fulda, Sergio Gascón, Stavroula K Hatzios, Valerian E Kagan, Kay Noel, Xuejun Jiang, Andreas Linkermann, Maureen E Murphy, Michael Overholtzer, Atsushi Oyagi, Gabriela C Pagnussat, Jason Park, Qitao Ran, Craig S Rosenfeld, Konstantin Salnikow, Daolin Tang, Frank M Torti, Suzy V Torti, Shinya Toyokuni, K A Woerpel, Donna D Zhang

Cell Vol. 171 ( 2 ) page： 273 - 285 2017.10

Language：English Publishing type：Research paper (scientific journal) Publisher：CELL PRESS

Ferroptosis is a form of regulated cell death characterized by the iron-dependent accumulation of lipid hydroperoxides to lethal levels. Emerging evidence suggests that ferroptosis represents an ancient vulnerability caused by the incorporation of polyunsaturated fatty acids into cellular membranes, and cells have developed complex systems that exploit and defend against this vulnerability in different contexts. The sensitivity to ferroptosis is tightly linked to numerous biological processes, including amino acid, iron, and polyunsaturated fatty acid metabolism, and the biosynthesis of glutathione, phospholipids, NADPH, and coenzyme Q(10). Ferroptosis has been implicated in the pathological cell death associated with degenerative diseases (i.e., Alzheimer's, Huntington's, and Parkinson's diseases), carcinogenesis, stroke, intracerebral hemorrhage, traumatic brain injury, ischemia-reperfusion injury, and kidney degeneration in mammals and is also implicated in heat stress in plants. Ferroptosis may also have a tumor-suppressor function that could be harnessed for cancer therapy. This Primer reviews the mechanisms underlying ferroptosis, highlights connections to other areas of biology and medicine, and recommends tools and guidelines for studying this emerging form of regulated cell death.

DOI： 10.1016/j.cell.2017.09.021

Osteogenic differentiation in dedifferentiated liposarcoma: a study of 36 cases in comparison to the cases without ossification. Reviewed

Yamashita K, Kohashi K, Yamada Y, Ishii T, Nishida Y, Urakawa H, Ito I, Takahashi M, Inoue T, Ito M, Ohara Y, Oda Y, Toyokuni S.

Histopathology 2017.10

Osteogenic differentiation in dedifferentiated liposarcoma: a study of 36 cases in comparison to the cases without ossification. Reviewed International journal

Yamashita K, Kohashi K, Yamada Y, Ishii T, Nishida Y, Urakawa H, Ito I, Takahashi M, Inoue T, Ito M, Ohara Y, Oda Y, Toyokuni S

Histopathology 2017.10

The iron chaperone poly(rC)-binding protein 2 forms a metabolon with the heme oxygenase 1/cytochrome P450 reductase complex for heme catabolism and iron transfer. Reviewed

Yanatori I, Richardson DR, Toyokuni S, Kishi F.

Journal of Biological Chemistry Vol. 292 ( 32 ) page： 13205-13229 2017.8

The iron chaperone poly(rC)-binding protein 2 forms a metabolon with the heme oxygenase 1/cytochrome P450 reductase complex for heme catabolism and iron transfer International journal

Izumi Yanatori, Des R. Richardson, Shinya Toyokuni, Fumio Kishi

JOURNAL OF BIOLOGICAL CHEMISTRY Vol. 292 ( 32 ) page： 13205 - 13229 2017.8

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

Mammals incorporate a major proportion of absorbed iron as heme, which is catabolized by the heme oxygenase 1 (HO1)-NADPH-cytochrome P450 reductase (CPR) complex into biliverdin, carbon monoxide, and ferrous iron. Moreover, intestinal iron is incorporated as ferrous iron, which is transported via the iron importer, divalent metal transporter 1 (DMT1). Recently, we demonstrated that the iron chaperone poly(rC)-binding protein 2 (PCBP2) can directly receive ferrous iron from DMT1 or transfer iron to the iron exporter, ferroportin 1. To promote intracellular iron flux, an iron chaperone may be essential for receiving iron generated by heme catabolism, but this hypothesis is untested so far. Herein, we demonstrate that HO1 binds to PCBP2, but not to other PCBP family members, namely PCBP1, PCBP3, or PCBP4. Interestingly, HO1 formed a complex with either CPR or PCBP2, and it was demonstrated that PCBP2 competes with CPR for HO1 binding. Using PCBP2-deletion mutants, we demonstrated that the PCBP2 K homology 3 domain is important for the HO1/PCBP2 interaction. In heme-loaded cells, heme prompted HO1-CPR complex formation and decreased the HO1/PCBP2 interaction. Furthermore, in vitro reconstitution experiments with purified recombinant proteins indicated that HO1 could bind to PCBP2 in the presence of heme, whereas loading of PCBP2 with ferrous iron caused PCBP2 to lose its affinity for HO1. These results indicate that ferrous iron released from heme can be bound by PCBP2 and suggest a model for an integrated heme catabolism and iron transport metabolon.

DOI： 10.1074/jbc.M117.776021

The iron chaperone poly(rC)-binding protein 2 forms a metabolon with the heme oxygenase 1/cytochrome P450 reductase complex for heme catabolism and iron transfer. Reviewed International journal

Yanatori I, Richardson DR, Toyokuni S, Kishi F

Journal of Biological Chemistry Vol. 292 ( 32 ) page： 13205-13229 2017.8

IRON OVERLOAD ENHANCED CELL DEATH INDUCED BY CARCINOGENIC FIBROUS MATERIALS

Ito Fumiya, Shi Lei, Toyokuni Shinya

AMERICAN JOURNAL OF HEMATOLOGY Vol. 92 ( 8 ) page： E365 - E365 2017.8

IRON OVERLOAD ENHANCED CELL DEATH INDUCED BY CARCINOGENIC FIBROUS MATERIALS International journal

Fumiya Ito, Lei Shi, Shinya Toyokuni

AMERICAN JOURNAL OF HEMATOLOGY Vol. 92 ( 8 ) page： E365 - E365 2017.8

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Papers - TOYOKUNI Shinya