Article
Oncology
Kazuko Kaneda-Nakashima, ZiJian Zhang, Yoshiyuki Manabe, Atsushi Shimoyama, Kazuya Kabayama, Tadashi Watabe, Yoshikatsu Kanai, Kazuhiro Ooe, Atsushi Toyoshima, Yoshifumi Shirakami, Takashi Yoshimura, Mitsuhiro Fukuda, Jun Hatazawa, Takashi Nakano, Koichi Fukase, Atsushi Shinohara
Summary: AMT has high affinity for LAT1, making At-211-AAMT a potential carrier for anti-cancer therapy by inhibiting tumor growth and inducing DNA double-stranded breaks. The accumulation of At-211-AAMT in vivo and its effectiveness in inhibiting tumor growth and metastasis suggest that At-211 could be useful for anti-cancer therapy, with LAT1 as a suitable target for radionuclide therapy.
Article
Oncology
Kou Nishikubo, Ryuichi Ohgaki, Xingming Liu, Hiroki Okanishi, Minhui Xu, Hitoshi Endou, Yoshikatsu Kanai
Summary: This study investigated the potential of combining the LAT1 inhibitor nanvuranlat with cytotoxic anticancer drugs. The results showed that nanvuranlat in combination with various cytotoxic anticancer drugs significantly inhibited the growth of pancreatic cancer cells, with gemcitabine showing the highest combination effect. Moreover, nanvuranlat also demonstrated growth inhibition in pancreatic and biliary tract cancer cells.
CANCER CELL INTERNATIONAL
(2023)
Review
Pharmacology & Pharmacy
Yoshikatsu Kanai
Summary: Cancer cells require a massive supply of nutrients, including amino acids. LAT1 is an amino acid transporter that is specifically expressed in cancer cells. High expression of LAT1 is associated with poor prognosis in patients. Inhibition of LAT1 can suppress cancer cell proliferation and tumor growth. LAT1 can also be used as a target for cancer diagnosis and specific delivery of anti-tumor drugs.
PHARMACOLOGY & THERAPEUTICS
(2022)
Article
Biochemistry & Molecular Biology
Johanna Huttunen, Mahmoud Agami, Janne Tampio, Ahmed B. Montaser, Kristiina M. Huttunen
Summary: l-Type amino acid transporter 1 (LAT1) is widely expressed in the brain and placenta, with overexpression in several cancer cell types. While the structure and ligand interactions of LAT1 are well-known, its intracellular life cycle remains poorly understood. The functionality of LAT1 can be measured using different methods, but variations between laboratories make result comparison challenging. This study evaluates the usefulness of indirect cis-inhibition methods and direct cellular uptake methods in interpreting LAT1-ligand interactions, highlighting the importance of understanding intracellular kinetics and their impact on critical tissues like the brain.
Article
Biochemistry & Molecular Biology
Yuta Shibasaki, Takehiko Yokobori, Makoto Sohda, Ikuma Shioi, Naoya Ozawa, Chika Komine, Kunihiko Suga, Nobuhiro Nakazawa, Katsuya Osone, Takuya Shiraishi, Takuhisa Okada, Akihiko Sano, Makoto Sakai, Hiroomi Ogawa, Kyoichi Kaira, Ken Shirabe, Hiroshi Saeki
Summary: The study focused on the regulatory mechanisms of mammalian target of rapamycin (mTOR) activation in cancers, specifically oxaliplatin-induced mTOR signaling and L-type amino acid transporter 1 (LAT1)-induced mTOR activation. It was found that high LAT1 expression in several cancers is associated with mTOR activation and chemotherapy resistance. The study investigated the significance of LAT1 in colorectal cancer (CRC) patients treated with adjuvant chemotherapy and found that LAT1 expression is associated with cancer aggressiveness and poor prognosis. LAT1 suppression in CRC cells inhibited proliferation, improved oxaliplatin sensitivity, and decreased mTOR signaling activation.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Gastroenterology & Hepatology
Cristina M. Hagen, Eva Roth, Theresia Reding Graf, Francois Verrey, Rolf Graf, Anurag Gupta, Giovanni Pellegrini, Nadege Poncet, Simone Mafalda Rodrigues Camargo
Summary: This study aimed to evaluate the role of LAT1 in the development and recovery of acute pancreatitis (AP). The results showed that LAT1 supports the regeneration of acinar cells after AP, with female mice lacking LAT1 exhibiting more pronounced alterations than male mice, indicating a sexual dimorphism in amino acid metabolism.
WORLD JOURNAL OF GASTROENTEROLOGY
(2022)
Article
Gastroenterology & Hepatology
Yunlong Sui, Namiko Hoshi, Ryuichi Ohgaki, Lingling Kong, Ryutaro Yoshida, Norihiro Okamoto, Masato Kinoshita, Haruka Miyazaki, Yuna Ku, Eri Tokunaga, Yuki Ito, Daisuke Watanabe, Makoto Ooi, Masakazu Shinohara, Kengo Sasaki, Yoh Zen, Takenori Kotani, Takashi Matozaki, Zibin Tian, Yoshikatsu Kanai, Yuzo Kodama
Summary: This study found that L-type amino acid transporter 1 (LAT1) is expressed constitutively in normal cells and plays an important role in tumor development and progression. The conditional deletion of LAT1 was shown to reduce the size and number of intestinal tumors and affect tumor initiation by reducing Wnt3 expression in Paneth cells. These findings partly explain how nutrient availability can influence the development of intestinal tumors.
JOURNAL OF GASTROENTEROLOGY
(2023)
Article
Biochemistry & Molecular Biology
Satish Kantipudi, Dimitrios Fotiadis
Summary: Studies have shown that 4F2hc-LAT1 is upregulated in cancer cells and serves as a potential anticancer target, while 4F2hc-LAT2 functions as a transporter in non-cancer cells. Cell assays are essential for determining the affinity and specificity of substrates and inhibitors for these transporters, providing valuable insights for drug development and disease research.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2021)
Review
Biochemistry & Molecular Biology
Francisca Dias, Cristina Almeida, Ana Luisa Teixeira, Mariana Morais, Rui Medeiros
Summary: The development and progression of colorectal cancer are associated with changes in amino acid transporters, with tumor cells upregulating certain transporters to support increased amino acid intake for growth and proliferation. While therapeutic approaches targeting these transporters have been attempted, none have reached clinical application yet. MiRNA-based therapies are gaining attention, with several drugs in clinical trials showing promising results.
Article
Biochemistry & Molecular Biology
Sun-Yee Kim, Qunxiang Ong, Yilie Liao, Zhaobing Ding, Alicia Qian Ler Tan, Ler Ting Rachel Lim, Hui Min Tan, Siew Lan Lim, Qian Yi Lee, Weiping Han
Summary: Through analysis of gene expression and dependency, LAT1 was identified as a top candidate supporting HCC tumorigenesis. Knockout of LAT1 decreased BCAA transport activity and cell proliferation in Huh7, and suppressed tumor growth in a xenograft model. LAT1 ablation reduced mTORC1 activity and cell proliferation, which were rescued by overexpression of LAT1. These findings highlight the essential role of LAT1 in tumor cell growth and potential therapeutic approaches for liver cancer.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Oncology
Chan Su Park, Min Je Sung, So Jeong Kim, Jung Hyun Jo, Hee Seung Lee, Moon Jae Chung, Seungmin Bang, Seung Woo Park, Si Young Song, Jeong Youp Park
Summary: This study aimed to explore the prognostic factors of pembrolizumab in patients with advanced biliary tract cancer (BTC) and provide treatment guidelines for patients who are refractory to gemcitabine-based chemotherapy. The results showed that high albumin levels and lymphocyte-to-monocyte ratio (LMR), as well as low alkaline phosphatase (ALP) levels and total bilirubin (TB), were significantly associated with better overall survival in patients treated with pembrolizumab.
Article
Biochemistry & Molecular Biology
Jussi Karkkainen, Tuomo Laitinen, Magdalena Markowicz-Piasecka, Ahmed Montaser, Marko Lehtonen, Jarkko Rautio, Mikko Gynther, Antti Poso, Kristiina M. Huttunen
Summary: LAT1 is a crucial protein that can be utilized for improved or targeted drug delivery and restricting amino acid supply from cancer cells. The study found differences in transport efficiency and affinity of compounds for LAT1, important for designing effective drug delivery methods.
BIOORGANIC CHEMISTRY
(2021)
Article
Oncology
Rafael S. Martinez, Mark J. Salji, Linda Rushworth, Chara Ntala, Giovanny Rodriguez Blanco, Ann Hedley, William Clark, Paul Peixoto, Eric Hervouet, Elodie Renaude, Sonia H. Y. Kung, Laura C. A. Galbraith, Colin Nixon, Sergio Lilla, Gillian M. Mackay, Ladan Fazli, Luke Gaughan, David Sumpton, Martin E. Gleave, Sara Zanivan, Arnaud Blomme, Hing Y. Leung
Summary: This study identified SLFN5 as a novel regulator of the LAT1 amino acid transporter in castration-resistant prostate cancer (CRPC), contributing to mTORC1 activity. High expression of SLFN5 in CRPC tumors was correlated with poor patient outcome, indicating its clinical relevance as a potential target for CRPC treatment.
Article
Cell Biology
Sayuki Iwahashi, Jiajun Lyu, Kazuya Tokumura, Ryoma Osumi, Manami Hiraiwa, Takuya Kubo, Tetsuhiro Horie, Satoru Demura, Noriaki Kawakami, Taku Saito, Gyujin Park, Kazuya Fukasawa, Takashi Iezaki, Akane Suzuki, Akane Tomizawa, Hiroki Ochi, Hironori Hojo, Shinsuke Ohba, Eiichi Hinoi
Summary: This study identifies LAT1 in chondrocytes as an important regulator of postnatal spinal homeostasis. The results show that loss of LAT1 in chondrocytes leads to severe thoracic scoliosis with disorganization of chondrocytes, increased apoptosis, and decreased cell proliferation. Furthermore, the study reveals that LAT1 regulates the general amino acid control pathway, rather than the mechanistic target of rapamycin complex 1 pathway, in chondrocytes.
JOURNAL OF CELLULAR PHYSIOLOGY
(2022)
Article
Medicine, Research & Experimental
Katayun Bahrami, Juulia Järvinen, Tuomo Laitinen, Mika Reinisalo, Paavo Honkakoski, Antti Poso, Kristiina M. Huttunen, Jarkko Rautio
Summary: In this study, a series of LAT1-targeted drug-phenylalanine conjugates were evaluated. Through in vitro studies and induced-fit docking, it was concluded that smaller compounds were preferred for uptake by LAT1. The flexibility of the ligand played a crucial role in determining the transportability and interactions with LAT1. Introducing polar groups enhanced interactions, while compounds with a carbamate bond in the para-position of the aromatic ring displayed efficient transport efficiencies. The findings of this study have implications for designing CNS or antineoplastic drug candidates and discovering LAT1 inhibitors for cancer therapy.
MOLECULAR PHARMACEUTICS
(2023)
Article
Rheumatology
Trang Thuy Dam, Hirofumi Hanaoka, Takahito Nakajima, Aiko Yamaguchi, Koichi Okamura, Hirotaka Chikuda, Yoshito Tsushima
Summary: The study evaluated the efficacy of radiopharmaceuticals targeting macrophage mannose receptors and hypoxia for early detection of rheumatoid arthritis in mice models. The results showed significant accumulation levels of the radiopharmaceuticals in inflamed joints, indicating their potential usefulness for imaging and early detection of RA.
MODERN RHEUMATOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Masaya Matsubayashi, Yoshihiko M. Sakaguchi, Yoshiki Sahara, Hitoki Nanaura, Sotaro Kikuchi, Arvand Asghari, Linh Bui, Shinko Kobashigawa, Mari Nakanishi, Riko Nagata, Takeshi K. Matsui, Genro Kashino, Masatoshi Hasegawa, Shin Takasawa, Masahiro Eriguchi, Kazuhiko Tsuruya, Shushi Nagamori, Kazuma Sugie, Takahiko Nakagawa, Minoru Takasato, Michihisa Umetani, Eiichiro Mori
Summary: In metabolic syndrome conditions, 27-hydroxycholesterol (27HC) can upregulate the uric acid reabsorption transporter URAT1 via estrogen receptors (ER) to increase uric acid reabsorption and potentially elevate serum uric acid levels.
Article
Radiology, Nuclear Medicine & Medical Imaging
Tatsuhiko Sato, Takuya Furuta, Yuwei Liu, Sadahiro Naka, Shushi Nagamori, Yoshikatsu Kanai, Tadashi Watabe
Summary: An individual dosimetry system was developed for nuclear medicine based on PHITS coupled with the microdosimetric kinetic model, enabling prediction of therapeutic and side effects of TAT. The system showed reliable performance in calculating organ doses from PET-CT images, with a significant decrease of EQDX(alpha/beta) for higher-activity injections in TAT. The system can utilize clinical data from external radiotherapy to enhance precision in nuclear medicine dosimetry.
Article
Biochemistry & Molecular Biology
Aiko Yamaguchi, Yasuaki Anami, Summer Y. Y. Ha, Travis J. Roeder, Wei Xiong, Jangsoon Lee, Naoto T. Ueno, Ningyan Zhang, Zhiqiang An, Kyoji Tsuchikama
Summary: Researchers developed and evaluated bispecific ADCs chemically functionalized with tumor-targeting small molecules, which can simultaneously target two different cancer antigens. These ADCs showed good stability and potential for effectively treating tumors with heterogeneous antigen expression.
BIOORGANIC & MEDICINAL CHEMISTRY
(2021)
Article
Multidisciplinary Sciences
Takuto Fujii, Takahiro Shimizu, Mizuki Katoh, Shushi Nagamori, Keiichi Koizumi, Junya Fukuoka, Yoshiaki Tabuchi, Akira Sawaguchi, Tomoyuki Okumura, Kazuto Shibuya, Tsutomu Fujii, Hiroshi Takeshima, Hideki Sakai
Summary: The study reveals that Na+,K+-ATPase alpha 3-isoform is translocated from intracellular vesicles to the plasma membrane of detached cancer cells, contributing to their survival. Focal-adhesion-kinase-dependent Ca2+ response induces alpha 3NaK translocation, associated with activation of AMP-activated protein kinase.
Article
Multidisciplinary Sciences
Chisato M. Yamazaki, Aiko Yamaguchi, Yasuaki Anami, Wei Xiong, Yoshihiro Otani, Jangsoon Lee, Naoto T. Ueno, Ningyan Zhang, Zhiqiang An, Kyoji Tsuchikama
Summary: In this study, dual-drug ADCs show promising therapeutic potential for treating heterogeneous breast tumors with minimal toxicity and optimal pharmacokinetic profiles. Compared to co-administration of two single-drug variants, the dual-drug ADC exhibits greater treatment effect and survival benefit in xenograft mouse models representing intratumor HER2 heterogeneity and drug resistance.
NATURE COMMUNICATIONS
(2021)
Article
Pharmacology & Pharmacy
Tomohisa Tanaka, Kaori Okuyama-Dobashi, Ryoji Motohashi, Hiromasa Yokoe, Kazunori Takahashi, Pattama Wiriyasermkul, Hirotake Kasai, Atsuya Yamashita, Shinya Maekawa, Nobuyuki Enomoto, Akihide Ryo, Shushi Nagamori, Masayoshi Tsubuki, Kohji Moriishi
Summary: Novel antivirals for treating chronic HBV infection are still needed, and in this study, compound 6 among 11 TZD derivatives showed the highest antiviral activity against HBV, while not affecting HCV infection. Compound 6 was found to inhibit HBV infection by interfering with the internalization process.
ANTIVIRAL RESEARCH
(2021)
Article
Biochemical Research Methods
Pornparn Kongpracha, Pattama Wiriyasermkul, Noriyoshi Isozumi, Satomi Moriyama, Yoshikatsu Kanai, Shushi Nagamori
Summary: Membrane proteins play crucial roles in cellular processes, and proteomics is a key method for exploring them. In this study, a membrane enrichment method using urea washing was found to significantly improve the identification of membrane proteins, especially transmembrane proteins.
MOLECULAR & CELLULAR PROTEOMICS
(2022)
Article
Cell Biology
Kana Hasegawa, Shunya Ikeda, Moto Yaga, Kouki Watanabe, Rika Urakawa, Akie Iehara, Mai Iwai, Seishin Hashiguchi, Soyoko Morimoto, Fumihiro Fujiki, Hiroko Nakajima, Jun Nakata, Sumiyuki Nishida, Akihiro Tsuboi, Yoshihiro Oka, Satoshi Yoshihara, Masahiro Manabe, Hiroyoshi Ichihara, Atsuko Mugitani, Yasutaka Aoyama, Takafumi Nakao, Asao Hirose, Masayuki Hino, Shiho Ueda, Katsuto Takenaka, Takashi Masuko, Koichi Akashi, Takahiro Maruno, Susumu Uchiyama, Shinji Takamatsu, Naoki Wada, Eiichi Morii, Shushi Nagamori, Daisuke Motooka, Yoshikatsu Kanai, Yusuke Oji, Tomoyoshi Nakagawa, Noriyuki Kijima, Haruhiko Kishima, Atsuyo Ikeda, Takayuki Ogino, Yasushi Shintani, Tateki Kubo, Emiko Mihara, Kosuke Yusa, Haruo Sugiyama, Junichi Takagi, Eiji Miyoshi, Atsushi Kumanogoh, Naoki Hosen
Summary: In this study, a monoclonal antibody (mAb) that specifically targets multiple myeloma (MM) cells by recognizing CD98 heavy chain (hc) was identified. The mAb, named R8H283, specifically bound to CD98hc in heterodimers but not monomers, leading to anti-MM effects without damaging normal hematopoietic cells. Furthermore, the study revealed the presence of a cancer-specific conformational epitope in a widely expressed protein, which can be found through extensive screening of primary human tumor samples.
SCIENCE TRANSLATIONAL MEDICINE
(2022)
Article
Biology
Tania Lopez-Hernandez, Koh-Ichiro Takenaka, Yasunori Mori, Pornparn Kongpracha, Shushi Nagamori, Volker Haucke, Shigeo Takamori
Summary: This study found that the endocytosis of synaptic vesicles in mouse hippocampal neurons at physiological temperature is independent of clathrin, while the endocytic retrieval of certain synaptic vesicle proteins, including vesicular transporters for glutamate and GABA, relies on sorting by the clathrin adaptor AP-2.
Article
Biochemistry & Molecular Biology
Yogi Umbarawan, Ryo Kawakami, Mas Rizky A. A. Syamsunarno, Hideru Obinata, Aiko Yamaguchi, Hirofumi Hanaoka, Takako Hishiki, Noriyo Hayakawa, Norimichi Koitabashi, Hiroaki Sunaga, Hiroki Matsui, Masahiko Kurabayashi, Tatsuya Iso
Summary: This study investigated the impact of CD36 knockout on STZ-induced diabetic cardiomyopathy, revealing that CD36KO-STZ hearts exhibited significant abnormalities in energy supply and glycolysis, leading to deteriorated cardiac function.
Article
Biochemistry & Molecular Biology
Takafumi Kawai, Hirotaka Narita, Kohtarou Konno, Sharmin Akter, Rizki Tsari Andriani, Hirohide Iwasaki, Shoji Nishikawa, Norihiko Yokoi, Yuko Fukata, Masaki Fukata, Pattama Wiriyasermkul, Pornparn Kongpracha, Shushi Nagamori, Keizo Takao, Tsuyoshi Miyakawa, Manabu Abe, Kenji Sakimura, Masahiko Watanabe, Atsushi Nakagawa, Yasushi Okamura
Summary: Voltage-sensing protein TMEM266 has a unique voltage-sensing mechanism and interacts with specific splice variants. The coiled-coil region plays a significant role in forming homodimers, and the cytosolic region at the C-terminal of TMEM266 may bind to various targets. TMEM266 deficiency is associated with behavioral abnormalities.
BIOCHEMICAL JOURNAL
(2022)
Article
Multidisciplinary Sciences
Yongchan Lee, Pattama Wiriyasermkul, Pornparn Kongpracha, Satomi Moriyama, Deryck J. Mills, Werner Kuhlbrandt, Shushi Nagamori
Summary: The study reveals the molecular basis of system b(0,+) biogenesis and type I cystinuria, by demonstrating the role of Ca2+ in stabilizing the interface between regulatory subunits and facilitating higher-order assembly. These findings provide valuable insights for understanding cystinuria and developing new therapeutic strategies, and also establish a connection between transporter oligomeric assembly and protein-trafficking diseases.
NATURE COMMUNICATIONS
(2022)
Article
Multidisciplinary Sciences
Sumire Sasaki, Yuji Shiozaki, Ai Hanazaki, Megumi Koike, Kazuya Tanifuji, Minori Uga, Kota Kawahara, Ichiro Kaneko, Yasuharu Kawamoto, Pattama Wiriyasermkul, Tomoka Hasegawa, Norio Amizuka, Ken-Ichi Miyamoto, Shushi Nagamori, Yoshikatsu Kanai, Hiroko Segawa
Summary: This study reveals the relationship between Tmem174, NaPi2a, and FGF23, and highlights the importance of Tmem174 in regulating FGF23 secretion in response to high Pi load in the bone and the regulation of NaPi2a.
SCIENTIFIC REPORTS
(2022)
Article
Multidisciplinary Sciences
Takuto Fujii, Shushi Nagamori, Pattama Wiriyasermkul, Shizhou Zheng, Asaka Yago, Takahiro Shimizu, Yoshiaki Tabuchi, Tomoyuki Okumura, Tsutomu Fujii, Hiroshi Takeshima, Hideki Sakai
Summary: Mutations in the human ATP13A2 gene are associated with the development of Parkinson's disease. This study reveals that ATP13A2 acts as a H+/K+ transporting protein in lysosomes, which prevents alkalization of lysosomes and accumulation of alpha-synuclein.
NATURE COMMUNICATIONS
(2023)
