Search

Your search keyword '"Tsunoda, Toshiyuki"' showing total 224 results
Start Over Author "Tsunoda, Toshiyuki"
224 results on '"Tsunoda, Toshiyuki"'

6. Oncogenic KRAS mutations enhance amino acid uptake by colorectal cancer cells via the hippo signaling effector YAP1

Author

Kandasamy, Palanivel, Zlobec, Inti, Nydegger, Damian T., Pujol-Gimenez, Jonai, Bhardwaj, Rajesh, Shirasawa, Senji, Tsunoda, Toshiyuki, and Hediger, Matthias A.

Subjects
Amino Acid Transport System ASC, solute carriers, congenital, hereditary, and neonatal diseases and abnormalities, SLC1A5/ASCT2, 610 Medicine & health, Minor Histocompatibility Antigens, Proto-Oncogene Proteins p21(ras), Mice, oncogene, Cell Line, Tumor, SLC38A2/SNAT2, Animals, Humans, Hippo Signaling Pathway, Amino Acids, neoplasms, Research Articles, RC254-282, SLC7A5/LAT1, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, YAP-Signaling Proteins, Fibroblasts, digestive system diseases, amino acid transporters, Mutation, 570 Life sciences, biology, Colorectal Neoplasms, Research Article
Abstract

Oncogenic KRAS mutations develop unique metabolic dependencies on nutrients to support tumor metabolism and cell proliferation. In particular, KRAS mutant cancer cells exploit amino acids (AAs) such as glutamine and leucine, to accelerate energy metabolism, redox balance through glutathione synthesis and macromolecule biosynthesis. However, the identities of the amino acid transporters (AATs) that are prominently upregulated in KRAS mutant cancer cells, and the mechanism regulating their expression have not yet been systematically investigated. Here, we report that the majority of the KRAS mutant colorectal cancer (CRC) cells upregulate selected AATs (SLC7A5/LAT1, SLC38A2/SNAT2, and SLC1A5/ASCT2), which correlates with enhanced uptake of AAs such as glutamine and leucine. Consistently, knockdown of oncogenic KRAS downregulated the expression of AATs, thereby decreasing the levels of amino acids taken up by CRC cells. Moreover, overexpression of mutant KRAS upregulated the expression of AATs (SLC7A5/LAT1, SLC38A2/SNAT2, and SLC1A5/ASCT2) in KRAS wild‐type CRC cells and mouse embryonic fibroblasts. In addition, we show that the YAP1 (Yes‐associated protein 1) transcriptional coactivator accounts for increased expression of AATs and mTOR activation in KRAS mutant CRC cells. Specific knockdown of AATs by shRNAs or pharmacological blockage of AATs effectively inhibited AA uptake, mTOR activation, and cell proliferation. Collectively, we conclude that oncogenic KRAS mutations enhance the expression of AATs via the hippo effector YAP1, leading to mTOR activation and CRC cell proliferation., Here, we demonstrate that oncogenic KRAS mutations upregulate the expression of selected amino acid transporters in colorectal cancer (CRC) cells through the hippo signaling effector YAP1. Upregulation of SLC1A5/ASCT2 and SLC38A2/SNAT2 led to intracellular l‐glutamine accumulation. l‐glutamine was reciprocally exported via SLC7A5/LAT1 in exchange for l‐leucine, a key activator of mTORC1. Intracellular l‐leucine led to the activation of mTORC1, thereby promoting KRAS mutant CRC cell proliferation.

Published
2021

10. Epipharyngeal Abrasive Therapy (EAT) Reduces the mRNA Expression of Major Proinflammatory Cytokine IL-6 in Chronic Epipharyngitis

Author

Nishi, Kensuke, primary, Yoshimoto, Shohei, additional, Nishi, Soichiro, additional, Nishi, Tatsuro, additional, Nishi, Ryushiro, additional, Tanaka, Takayuki, additional, Tsunoda, Toshiyuki, additional, Imai, Kazuaki, additional, Tanaka, Hiroaki, additional, Hotta, Osamu, additional, Tanaka, Ayaki, additional, Hiromatsu, Kenji, additional, Shirasawa, Senji, additional, Nakagawa, Takashi, additional, and Yamano, Takafumi, additional

Published
2022
Full Text
View/download PDF

11. Standardized Methods Using EUS-guided Fine-needle Biopsy and a Minimal Medium Creates Three Pancreatic Cancer Organoids

Author

ISHIDA, YUSUKE, primary, TSUNODA, TOSHIYUKI, additional, HAMADA, YOSHIHIRO, additional, TSUCHIYA, NAOAKI, additional, KOGA, TAKEHIKO, additional, KITAGUCHI, TAKANORI, additional, MATSUMOTO, KEISUKE, additional, MATSUMOTO, SHINJI, additional, SASAKI, TAKAHIDE, additional, NAKASHIMA, RYO, additional, ISHII, FUMINORI, additional, KAJIWARA, MASATOSHI, additional, SHIRASAWA, SENJI, additional, HASEGAWA, SUGURU, additional, and HIRAI, FUMIHITO, additional

Published
2022
Full Text
View/download PDF

14. Cryptotanshinone suppresses tumorigenesis by inhibiting lipogenesis and promoting reactive oxygen species production in KRAS‑activated pancreatic cancer cells

Author

Terado, Tokio, primary, Kim, Chul, additional, Ushio, Akiyo, additional, Minami, Kahori, additional, Tambe, Yukihiro, additional, Kageyama, Susumu, additional, Kawauchi, Akihiro, additional, Tsunoda, Toshiyuki, additional, Shirasawa, Senji, additional, Tanaka, Hiroyuki, additional, and Inoue, Hirokazu, additional

Published
2022
Full Text
View/download PDF

15. Epipharyngeal Abrasive Therapy (EAT) Has Potential as a Novel Method for Long COVID Treatment

Author

Imai, Kazuaki, primary, Yamano, Takafumi, additional, Nishi, Soichiro, additional, Nishi, Ryushiro, additional, Nishi, Tatsuro, additional, Tanaka, Hiroaki, additional, Tsunoda, Toshiyuki, additional, Yoshimoto, Shohei, additional, Tanaka, Ayaki, additional, Hiromatsu, Kenji, additional, Shirasawa, Senji, additional, Nakagawa, Takashi, additional, and Nishi, Kensuke, additional

Published
2022
Full Text
View/download PDF

17. Epipharyngeal Abrasive Therapy Down-regulates the Expression of Cav1.2: A Key Molecule in Influenza Virus Entry

Author

NISHI, KENSUKE, primary, YOSHIMOTO, SHOHEI, additional, NISHI, SOICHIRO, additional, NISHI, TATSURO, additional, NISHI, RYUSHIRO, additional, TSUNODA, TOSHIYUKI, additional, MORITA, HIROMITSU, additional, TANAKA, HIROAKI, additional, HOTTA, OSAMU, additional, YASUMASU, SUSUMU, additional, HIROMATSU, KENJI, additional, SHIRASAWA, SENJI, additional, NAKAGAWA, TAKASHI, additional, and YAMANO, TAKAFUMI, additional

Published
2022
Full Text
View/download PDF

30. Mutant KRAS Promotes NKG2D+ T Cell Infiltration and CD155 Dependent Immune Evasion

Author

NISHI, KENSUKE, primary, ISHIKURA, SHUHEI, additional, UMEBAYASHI, MASAYO, additional, MORISAKI, TAKASHI, additional, INOZUME, TAKASHI, additional, KINUGASA, TETSUSHI, additional, AOKI, MIKIKO, additional, NIMURA, SATOSHI, additional, SWAIN, ANTHONY, additional, YOSHIDA, YOICHIRO, additional, HASEGAWA, SUGURU, additional, NABESHIMA, KAZUKI, additional, SAKATA, TOSHIFUMI, additional, SHIRASAWA, SENJI, additional, and TSUNODA, TOSHIYUKI, additional

Published
2020
Full Text
View/download PDF

36. Inhibition of Phosphodiesterase-4 (PDE4) activity triggers luminal apoptosis and AKT dephosphorylation in a 3-D colonic-crypt model

Author

Tsunoda Toshiyuki, Ota Takeharu, Fujimoto Takahiro, Doi Keiko, Tanaka Yoko, Yoshida Yasuhiro, Ogawa Masahiro, Matsuzaki Hiroshi, Hamabashiri Masato, Tyson Darren R, Kuroki Masahide, Miyamoto Shingo, and Shirasawa Senji

Subjects
PDE4B, Three-dimensional culture, Colorectal cancer, Kras, AKT, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background We previously established a three-dimensional (3-D) colonic crypt model using HKe3 cells which are human colorectal cancer (CRC) HCT116 cells with a disruption in oncogenic KRAS, and revealed the crucial roles of oncogenic KRAS both in inhibition of apoptosis and in disruption of cell polarity; however, the molecular mechanism of KRAS-induced these 3-D specific biological changes remains to be elucidated. Results Among the genes that were upregulated by oncogenic KRAS in this model, we focused on the phosphodiesterase 4B (PDE4B) of which expression levels were found to be higher in clinical tumor samples from CRC patients in comparison to those from healthy control in the public datasets of gene expression analysis. PDE4B2 was specifically overexpressed among other PDE4 isoforms, and re-expression of oncogenic KRAS in HKe3 cells resulted in PDE4B overexpression. Furthermore, the inhibition of PDE4 catalytic activity using rolipram reverted the disorganization of HCT116 cells into the normal physiologic state of the epithelial cell polarity by inducing the apical assembly of ZO-1 (a tight junction marker) and E-cadherin (an adherens junction marker) and by increasing the activity of caspase-3 (an apoptosis marker) in luminal cavities. Notably, rolipram reduced the AKT phosphorylation, which is known to be associated with the disruption of luminal cavity formation and CRC development. Similar results were also obtained using PDE4B2-shRNAs. In addition, increased expression of PDE4B mRNA was found to be correlated with relapsed CRC in a public datasets of gene expression analysis. Conclusions These results collectively suggested that PDE4B is upregulated by oncogenic KRAS, and also that the inhibition of PDE4 catalytic activity can induce both epithelial cell polarity and luminal apoptosis in CRC, thus highlighting the utility of our 3-D culture (3 DC) model for the KRAS-induced development of CRC in 3-D microenvironment. Indeed, using this model, we found that PDE4B is a promising candidate for a therapeutic target as well as prognostic molecular marker in CRC. Further elucidation of the signaling network of PDE4B2 in 3 DC would provide a better understanding of CRC in vivo.

Published
2012
Full Text
View/download PDF

45. Transcriptional and metabolic rewiring of colorectal cancer cells expressing the oncogenic KRASG13D mutation.

Author

Charitou, Theodosia, Srihari, Sriganesh, Lynn, Miriam A., Jarboui, Mohamed-Ali, Fasterius, Erik, Moldovan, Max, Shirasawa, Senji, Tsunoda, Toshiyuki, Ueffing, Marius, Xie, Jianling, Xin, Jin, Wang, Xuemin, Proud, Christopher G., Boldt, Karsten, Al-Khalili Szigyarto, Cristina, Kolch, Walter, and Lynn, David J.

Abstract

Background: Activating mutations in KRAS frequently occur in colorectal cancer (CRC) patients, leading to resistance to EGFR-targeted therapies.Methods: To better understand the cellular reprogramming which occurs in mutant KRAS cells, we have undertaken a systems-level analysis of four CRC cell lines which express either wild type (wt) KRAS or the oncogenic KRASG13D allele (mtKRAS).Results: RNAseq revealed that genes involved in ribosome biogenesis, mRNA translation and metabolism were significantly upregulated in mtKRAS cells. Consistent with the transcriptional data, protein synthesis and cell proliferation were significantly higher in the mtKRAS cells. Targeted metabolomics analysis also confirmed the metabolic reprogramming in mtKRAS cells. Interestingly, mtKRAS cells were highly transcriptionally responsive to EGFR activation by TGFα stimulation, which was associated with an unexpected downregulation of genes involved in a range of anabolic processes. While TGFα treatment strongly activated protein synthesis in wtKRAS cells, protein synthesis was not activated above basal levels in the TGFα-treated mtKRAS cells. This was likely due to the defective activation of the mTORC1 and other pathways by TGFα in mtKRAS cells, which was associated with impaired activation of PKB signalling and a transient induction of AMPK signalling.Conclusions: We have found that mtKRAS cells are substantially rewired at the transcriptional, translational and metabolic levels and that this rewiring may reveal new vulnerabilities in oncogenic KRAS CRC cells that could be exploited in future. [ABSTRACT FROM AUTHOR]

Published
2019
Full Text
View/download PDF

46. Molecular mechanisms of transcriptional regulation by the nuclear zinc-finger protein Zfat in T cells

Author

Ishikura, Shuhei, primary, Tsunoda, Toshiyuki, additional, Nakabayashi, Kazuhiko, additional, Doi, Keiko, additional, Koyanagi, Midori, additional, Hayashi, Keiko, additional, Kawai, Tomoko, additional, Tanaka, Yoko, additional, Iwaihara, Yuri, additional, Luo, Hao, additional, Nishi, Kensuke, additional, Okamura, Tadashi, additional, and Shirasawa, Senji, additional

Published
2016
Full Text
View/download PDF

50. Three-dimensionally Specific Inhibition of DNA Repair-Related Genes by Activated KRAS in Colon Crypt Model1 2

Author

Tsunoda, Toshiyuki, Takashima, Yasuo, Fujimoto, Takahiro, Koyanagi, Midori, Yoshida, Yasuhiro, Doi, Keiko, Tanaka, Yoko, Kuroki, Masahide, Sasazuki, Takehiko, and Shirasawa, Senji

Subjects
Microscopy, Confocal, DNA Repair, Reverse Transcriptase Polymerase Chain Reaction, Gene Expression Profiling, Blotting, Western, Cell Culture Techniques, Fluorescent Antibody Technique, Gene Expression, Apoptosis, Models, Biological, digestive system diseases, Proto-Oncogene Proteins p21(ras), DNA Repair Enzymes, Cell Line, Tumor, Proto-Oncogene Proteins, ras Proteins, Humans, Intestinal Mucosa, Colorectal Neoplasms, neoplasms, Research Article
Abstract

Growth and differentiation of colonic epithelium are regulated in the three-dimensional (3D) physiological architecture, colonic crypt, and deregulation of 3D interactions is involved in tumorigenesis. Cell-based 3D culture systems provide a suitable approach bridging the gap between two-dimensional (2D) culture and animal models. KRAS mutations are found at high frequencies in human colorectal cancer (CRC); however, KRAS-targeted cancer therapy has not been developed. Here, we have established a 3D cell culture model resembling the colonic crypt by use of HKe3 cells, human CRC HCT116 cells disrupted at activated KRAS. In this 3D colonic crypt model, HKe3 cells showed the features of time course-dependent transit-amplifying and terminal-differentiated stages, which are characteristic of normal colonic crypt. On the basis of the features of HCT116 cells, activated KRAS inhibited normal cell polarity and apoptosis in 3D culture. The expression of DNA repair-related tumor suppressor genes including TP53, BRCA1, BRCA2, and EXO-1 was markedly suppressed by activated KRAS in 3D culture but not in 2D culture. These results together suggest that activated KRAS plays critical roles in the accumulation of genetic alterations through inhibition of DNA repair genes and apoptosis and that this 3D culture model will provide a useful tool for investigating the molecular mechanisms of CRC development.

Published
2010

Catalog

Books, media, physical & digital resources
See catalog results