Article
Oncology
George Sharbeen, Joshua A. McCarroll, Anouschka Akerman, Chantal Kopecky, Janet Youkhana, John Kokkinos, Jeff Holst, Cyrille Boyer, Mert Erkan, David Goldstein, Paul Timpson, Thomas R. Cox, Brooke A. Pereira, Jessica L. Chitty, Sigrid K. Fey, Arafath K. Najumudeen, Andrew D. Campbell, Owen J. Sansom, Rosa Mistica C. Ignacio, Stephanie Naim, Jie Liu, Nelson Russia, Julia Lee, Angela Chou, Amber Johns, Anthony J. Gill, Estrella Gonzales-Aloy, Val Gebski, Yi Fang Guan, Marina Pajic, Nigel Turner, Minoti Apte, Thomas P. Davis, Jennifer P. Morton, Koroush S. Haghighi, Jorjina Kasparian, Benjamin J. McLean, Yordanos F. Setargew, Phoebe A. Phillips
Summary: High expression of SLC7A11 in human PDAC tumor stroma, independently prognostic of poorer overall survival. The study demonstrates that PDAC-derived CAFs are highly dependent on SLC7A11 for cystine uptake and glutathione synthesis. Inhibition of SLC7A11 decreases CAF proliferation, reduces their resistance to oxidative stress, and inhibits their ability to support PDAC cell growth.
Article
Chemistry, Medicinal
Zhe Li, Xin Qiao, Xiao-Meng Liu, Shu-Hao Shi, Jing-Yuan Xu
Summary: In this study, riluzole-Pt(IV) compounds were synthesized to target multiple pathways and achieve a synergistic anticancer effect. Compound 2 showed excellent antiproliferative activity and selectivity compared to cisplatin. Mechanism studies revealed that compound 2 released riluzole and active Pt(II) species, leading to DNA damage, cell apoptosis, and inhibition of metastasis. It also blocked glutathione biosynthesis and targeted hERG1, suppressing cancer cell growth and reversing EMT. These riluzole-Pt(IV) prodrugs are promising candidates for cancer treatment compared to traditional platinum drugs.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Review
Endocrinology & Metabolism
Ana Cristina Garcia-Gaytan, Andy Hernandez-Abrego, Mauricio Diaz-Munoz, Isabel Mendez
Summary: This article discusses the importance of glutamate in the body, particularly its role in tumor growth and cancer research. The expression of glutamate receptors and transporters may be related to tumor metastasis and could potentially serve as therapeutic targets and biomarkers for cancer treatment.
FRONTIERS IN ENDOCRINOLOGY
(2022)
Article
Neurosciences
Pauline Beckers, Olaya Lara, Ines Belo do Nascimento, Nathalie Desmet, Ann Massie, Emmanuel Hermans
Summary: Disruption of glutamatergic homeostasis is commonly observed in neurological diseases. The role of cystine-glutamate exchanger system x(c)(-) in controlling glutamate transmission is gaining interest. This study validates a method using tritiated glutamate as a substrate for the reversed transport mediated by system x(c)(-), providing a robust and cost-efficient solution to investigate the activity of this exchanger in physiological and pathological conditions. It also serves as a reliable tool for screening and characterization of new system x(c)(-) inhibitors.
FRONTIERS IN CELLULAR NEUROSCIENCE
(2022)
Article
Chemistry, Multidisciplinary
Takashi Shimomura, Norio Hirakawa, Yuya Ohuchi, Munetaka Ishiyama, Masanobu Shiga, Yuichiro Ueno
Summary: A method to measure xCT activity using selenocysteine and FOdA reaction has been developed in this study, which can evaluate the cystine uptake activity of xCT in different cells and the inhibitory efficiency of xCT inhibitors.
Article
Ophthalmology
Renita Maria Martis, Bo Li, Paul James Donaldson, Julie Ching-Hsia Lim
Summary: The study found that loss of xCT resulted in depletion of glutathione in the epithelium and an oxidative shift in the cysteine/cystine ratio of the aqueous humor, accelerating the development of an anterior cataract in knockout mice.
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE
(2021)
Article
Multidisciplinary Sciences
Joanne L. Parker, Justin C. Deme, Dimitrios Kolokouris, Gabriel Kuteyi, Philip C. Biggin, Susan M. Lea, Simon Newstead
Summary: The study presents the cryo-EM structure of human system xc- in both apo and glutamate bound states, discussing its cystine transport mechanism and highlighting its potential as a target for anticancer therapies due to its role in cellular redox homeostasis. The research shows an allosteric mechanism for ligand discrimination in system xc(-) supported by molecular dynamics and cell-based assays, establishing a mechanism for cystine transport in human cells.
NATURE COMMUNICATIONS
(2021)
Article
Neurosciences
Bradley S. Heit, Alex Chu, Abhay Sane, David E. Featherstone, Thomas J. Park, John Larson
Summary: Stroke-induced release of glutamate triggers anoxic depolarization (AD) and rapid cell death. Tonic glutamate, regulated by the system x(c)(-), has a significant effect on the latency of AD events and subsequent tissue damage. Transgenic mice lacking the system x(c)(-) exhibit longer AD latencies and altered depolarizing waves after oxygen deprivation, highlighting the role of ambient glutamate in the pathogenesis of acute stroke.
JOURNAL OF PHYSIOLOGY-LONDON
(2023)
Article
Cell Biology
Ren Watanabe, Tomoe Takano, Sho Sasaki, Mizuho Obara, Ken Umeno, Hideyo Sato, Naoko Kimura
Summary: Our study on xCTKO mice revealed that they are able to maintain a high follicle reserve after puberty, resulting in the preservation of fertility. This could be attributed to the suppression of follicle activation during the neonatal period.
HISTOCHEMISTRY AND CELL BIOLOGY
(2022)
Review
Cell Biology
Pranavi Koppula, Li Zhuang, Boyi Gan
Summary: The overexpression of SLC7A11 promotes tumor growth while causing significant metabolic reprogramming costs for cancer cells. Cancer cells with high expression of SLC7A11 exhibit glucose- and glutamine-dependency, presenting potential metabolic vulnerabilities for therapeutic targeting.
Article
Pharmacology & Pharmacy
Keisuke Okamoto, Yoshitaka Saito, Hinata Ueda, Katsuya Narumi, Ayako Furugen, Masaki Kobayashi
Summary: This study investigated the kinetics of xCT in A549 cells and the inhibition pattern of sulfasalazine for cystine uptake. It found that cystine uptake was time-dependent and sulfasalazine inhibited it in a concentration-dependent manner, showing a mixed inhibition pattern. Additionally, xCT siRNA decreased xCT mRNA levels and reduced cystine uptake in A549 cells.
BIOPHARMACEUTICS & DRUG DISPOSITION
(2021)
Article
Pharmacology & Pharmacy
You-Cong Yin, Xiao-hui Li, Xuan Rao, Yuan-Jian Li, Jie Du
Summary: An increasing number of studies have shown that miRNAs play an important role in regulating stress-induced ulcers. This study found that miR-143, miR-152, and miR-181 are involved in cold stimulation-induced acute gastric mucosal injury, and their regulatory effect is related to a decrease in glutamate release by reduction of cystine/glutamate transporter activity.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Cell Biology
Jinfu Zhuang, Xing Liu, Yuanfeng Yang, Yiyi Zhang, Guoxian Guan
Summary: The study revealed that xCT is up-regulated in gastric cancer and is associated with tumor stage and patient prognosis. Sulfasalazine can attenuate the proliferation, colony formation, migration, and invasion of gastric cancer cells.
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
(2021)
Article
Physiology
Michele Galluccio, Mariafrancesca Scalise, Gilda Pappacoda, Martina Scarpelli, Marcella Bonanomi, Daniela Gaglio, Cesare Indiveri
Summary: The plasma membrane transporter xCT plays a crucial role in the exchange of glutamate and cystine across the cell membrane and is a target of interest for cancer research. In this study, the human isoform of xCT was successfully over-expressed in Escherichia coli and subsequently purified for functional and kinetic characterization. The findings suggest that E. coli can be used as a suitable host for the expression of human proteins, providing a useful model for studying xCT biology.
FRONTIERS IN PHYSIOLOGY
(2022)
Article
Pharmacology & Pharmacy
Lise Verbruggen, Lindsay Sprimont, Eduard Bentea, Pauline Janssen, Azzedine Gharib, Lauren Deneyer, Laura De Pauw, Olaya Lara, Hideyo Sato, Charles Nicaise, Ann Massie
Summary: Despite chronic administration of SAS to mice, no undesirable system x(c)(-)-dependent effects were identified. SAS had negative impacts on survival rate, body weight, thermoregulation, and stress reaction in both genotypes, independent of its inhibitory action on system x(c)(-). While SAS decreased total distance traveled in open-field test initially, it did not have long-term effects or induce changes in anxiety- or depressive-like behavior. Additionally, no major histological abnormalities were observed in the spinal cord.
FRONTIERS IN PHARMACOLOGY
(2021)
Article
Oncology
Yuji Otsuki, Juntaro Yamasaki, Kentaro Suina, Shogo Okazaki, Naoyoshi Koike, Hideyuki Saya, Osamu Nagano
Article
Cell Biology
Haruko Kunitomi, Yoshinao Oki, Nobuyuki Onishi, Koichiro Kano, Kouji Banno, Daisuke Aoki, Hideyuki Saya, Hiroyuki Nobusue
Review
Oncology
Mari Hosonaga, Hideyuki Saya, Yoshimi Arima
CANCER AND METASTASIS REVIEWS
(2020)
Article
Oncology
Yoshimi Arima, Hiroyuki Nobusue, Hideyuki Saya
Article
Multidisciplinary Sciences
Kenji Shono, Izumi Yamaguchi, Yoshifumi Mizobuchi, Hiroshi Kagusa, Akiko Sumi, Toshitaka Fujihara, Kohei Nakajima, Keiko T. Kitazato, Kazuhito Matsuzaki, Hideyuki Saya, Yasushi Takagi
SCIENTIFIC REPORTS
(2020)
Article
Multidisciplinary Sciences
Ikue Tai-Nagara, Yukiko Hasumi, Dai Kusumoto, Hisashi Hasumi, Keisuke Okabe, Tomofumi Ando, Fumio Matsuzaki, Fumiko Itoh, Hideyuki Saya, Chang Liu, Wenling Li, Yoh-suke Mukouyama, W. Marston Linehan, Xinyi Liu, Masanori Hirashima, Yutaka Suzuki, Shintaro Funasaki, Yorifumi Satou, Mitsuko Furuya, Masaya Baba, Yoshiaki Kubota
NATURE COMMUNICATIONS
(2020)
Article
Virology
Masaru Takeshita, Naoshi Nishina, Saya Moriyama, Yoshimasa Takahashi, Yoshifumi Uwamino, Mika Nagata, Wataru Aoki, Katsunori Masaki, Makoto Ishii, Hideyuki Saya, Yasushi Kondo, Yuko Kaneko, Katsuya Suzuki, Koichi Fukunaga, Tsutomu Takeuchi
Summary: The study found that asymptomatic and mild COVID-19 patients had inadequate humoral immune responses, with most antibodies being correlated with disease severity, symptoms such as pneumonia, lymphopenia, and certain serological markers, and some patients failing to develop antibodies against the virus.
Article
Biochemistry & Molecular Biology
Toshikatsu Tsuji, Yusuke Maeda, Kenji Kita, Kazuhiro Murakami, Hideyuki Saya, Hirofumi Takemura, Noriyuki Inaki, Masanobu Oshima, Hiroko Oshima
Summary: The study found that FOXO3 displays different expression patterns in different subtypes of gastric cancer: in FOXO3-Cyt gastric cancer cells, activation of mutant FOXO3 leads to nuclear accumulation and growth inhibition, while inhibition of the PI3K-AKT pathway also suppresses proliferation in this type of gastric cancer cells.
Article
Oncology
Ryo Sato, Kosuke Imamura, Takashi Semba, Yusuke Tomita, Sho Saeki, Koei Ikeda, Yoshihiro Komohara, Makoto Suzuki, Takuro Sakagami, Hideyuki Saya, Yoshimi Arima
Summary: CAF secrete TGF beta to induce a solid-to-acinar transition in lung cancer cells, demonstrating how the tumor microenvironment influences histological patterns and tumor heterogeneity in lung adenocarcinoma.
Review
Cell & Tissue Engineering
Go J. Yoshida, Hideyuki Saya
Summary: Intratumoral heterogeneity is closely linked to treatment failure in cancer, with cancer stem cells (CSCs) playing a key role in this process. CSCs, located at the top of the tumor cell hierarchy, possess self-renewal and therapeutic resistance capabilities, contributing to the challenges in cancer therapy.
REGENERATIVE THERAPY
(2021)
Article
Oncology
Juntaro Yamasaki, Yuki Hirata, Yuji Otsuki, Kentaro Suina, Yoshiyuki Saito, Kenta Masuda, Shogo Okazaki, Takatsugu Ishimoto, Hideyuki Saya, Osamu Nagano
Summary: Metastatic progression of tumors is driven by genetic alterations and tumor-stroma interaction. Using an organoid-based model of gastric cancer, researchers studied the mechanism underlying the metastasis of KRAS-mutated gastric cancer and found that an inhibitor of MAPK signaling could suppress metastasis.
Article
Biology
Sayaka Ueno, Tamotsu Sudo, Hideyuki Saya, Eiji Sugihara
Summary: This study reveals that pigment epithelium-derived factor (PEDF) promotes the dissemination of ovarian cancer by inducing IL-10 expression in macrophages. High PEDF gene expression is associated with poor prognosis in ovarian cancer patients, and elevated PEDF levels are correlated with early recurrence. BET inhibitors reduce PEDF expression and limit both cancer cell survival and macrophage induction.
COMMUNICATIONS BIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Haruki Inoue, Eriko Aimono, Akiyoshi Kasuga, Haruto Tanaka, Aika Iwasaki, Hideyuki Saya, Yoshimi Arima
Summary: Our mouse BTC models are suitable for studying BTC carcinogenesis and may contribute to the development of new therapeutic strategies. Analysis of images of mouse and human tumor tissues reveals similarities in tissue structure between the two, suggesting similarities in tumor characteristics independent of animal species. Additionally, our pixel-level clustering model can serve as a new diagnostic tool for BTC.
Article
Medicine, Research & Experimental
Fumimasa Kitamura, Takashi Semba, Noriko Yasuda-Yoshihara, Kosuke Yamada, Akiho Nishimura, Juntaro Yamasaki, Osamu Nagano, Tadahito Yasuda, Atsuko Yonemura, Yilin Tong, Huaitao Wang, Takahiko Akiyama, Kazuki Matsumura, Norio Uemura, Rumi Itoyama, Luke Bu, Lingfeng Fu, Xichen Hu, Feng Wei, Kosuke Mima, Katsunori Imai, Hiromitsu Hayashi, Yo-ichi Yamashita, Yuji Miyamoto, Hideo Baba, Takatsugu Ishimoto
Summary: Glycolysis is increased in pancreatic ductal adenocarcinoma (PDAC) cells, resulting in glucose restrictions on nontumor cells in the tumor microenvironment. Cancer-associated fibroblasts (CAFs) with restricted glucose availability utilize lactate as a fuel and exhibit immunosuppressive activity in the PDAC microenvironment. Coculture experiments revealed that glucose is mainly consumed by tumor cells, while CAFs consume lactate through monocarboxylate transporter 1 to enhance proliferation. Lactate-stimulated CAFs upregulate IL-6 expression and synergistically suppress cytotoxic immune cell activity with lactate. Inhibiting lactate dehydrogenase A (LDHA) reduces tumor growth and improves antitumor immunity in CAF-rich PDAC tumors.
Article
Medicine, Research & Experimental
Tomofumi Ando, Ikue Tai-Nagara, Yuki Sugiura, Dai Kusumoto, Koji Okabayashi, Yasuaki Kido, Kohji Sato, Hideyuki Saya, Sutip Navankasattusas, Dean Y. Li, Makoto Suematsu, Yuko Kitagawa, Elena Seiradake, Satoru Yamagishi, Yoshiaki Kubota
Summary: Blood vessel abnormalities in cancer can be targeted therapeutically to suppress cancer progression, according to a study. Researchers found that a molecule called fibronectin leucine-rich transmembrane protein 2 (FLRT2) is expressed in abnormal blood vessels of advanced colorectal cancers in humans. Deleting FLRT2 in endothelial cells selectively pruned abnormal blood vessels and suppressed tumor metastasis. Additionally, FLRT2 deletion increased the number of mature vessels, enhancing the antitumor effects of immune checkpoint blockers. The study suggests that targeting tumor-specific interendothelial adhesions could be a safe and effective therapeutic option.
JOURNAL OF CLINICAL INVESTIGATION
(2022)