Article
Chemistry, Medicinal
Molly Congdon, Russell G. Fritzemeier, Yugesh Kharel, Anne M. Brown, Vlad Serbulea, David R. Bevan, Kevin R. Lynch, Webster L. Santos
Summary: Elevated levels of Sphingosine 1-phosphate (S1P) and increased expression of Sphingosine kinase iso-forms (SphK1 and SphK2) are associated with various disease states. The development of selective inhibitors for SphK1 and SphK2 has become a focus of drug discovery, with studies focusing on optimizing binding in the SphK2 substrate binding site. The identification of indole-based compounds with 1,5-disubstitution as potent inhibitors highlights the potential for targeting SphK2 with improved potency and selectivity.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Redona Hafizi, Faik Imeri, Bisera Stepanovska Tanturovska, Roxana Manaila, Stephanie Schwalm, Sandra Trautmann, Roland H. Wenger, Josef Pfeilschifter, Andrea Huwiler
Summary: The study demonstrated that sphingolipids have diverse effects on Epo synthesis, with accumulation of intracellular Sph reducing Epo synthesis, while iS1P enhanced Epo synthesis through S1P(1+3) receptors. Selective inhibition of Sphk2 appears to be a promising approach to increase Epo synthesis and reduce anemia development in chronic kidney disease.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Multidisciplinary Sciences
David Martin-Hernandez, Irene L. Gutierrez, Marta Gonzalez-Prieto, Karina S. MacDowell, Javier Robledo-Montana, Hiram Tendilla-Beltran, Natalia Calleja-Rodriguez, Alvaro G. Bris, Cristina Ulecia-Moron, Beatriz Moreno, Javier R. Caso, Borja Garcia-Bueno, Sandra Rodrigues-Mascarenhas, Ignacio Marin-Jimenez, Juan Carlos Leza, Luis Menchen
Summary: The chronic inflammatory process in inflammatory bowel diseases (IBD) is mainly driven by T-cell response to microbial and environmental antigens. Psychological stress can trigger clinical flares of IBD, and sphingosine-1-phosphate (S1P) is involved in T-cell recruitment. By evaluating the impact of stress and the absence of sphingosine kinase 2 (Sphk2) on the colon of mice, it was found that stress increased S1P levels in the colon, possibly due to decreased degradation enzymes and Sphk2. This S1P accumulation could lead to inflammation and immune dysregulation, contributing to the development of IBD.
SCIENTIFIC REPORTS
(2022)
Article
Medicine, General & Internal
Lan Dai, Chen Wang, Wenjing Wang, Keqi Song, Taiyang Ye, Jie Zhu, Wen Di
Summary: This study reveals the involvement of adipocytes in promoting the growth of epithelial ovarian cancer (EOC) and identifies sphingosine kinase 2 (SphK2) as a key mediator in this process. Inhibition of SphK2 significantly suppresses adipocyte-induced EOC cell proliferation, which is dependent on the activation of extracellular signal-regulated protein kinases (ERK). Furthermore, silencing SphK2 inhibits the adipocyte-induced expression of phospho-ERK and c-Myc, two crucial factors in EOC growth.
Article
Biochemistry & Molecular Biology
Xixi Chen, Liping Wang, Xiao Yu, Shujing Wang, Jianing Zhang
Summary: In this study, it was found that Cav-1 upregulated ST6Gal-I to promote migration and invasion of HCC cells through inducing epithelial-to-mesenchymal transition. The activation of the PI3K/AKT/mTOR signaling pathway and the binding of NR4A2/RXRα to the ST6GAL1 promoter region were critical for Cav-1-induced ST6GAL1 gene expression. These findings provide insights into the mechanism of ST6GAL1 gene transcription regulated by Cav-1, potentially leading to the development of novel therapeutic strategies targeting metastasis in HCC.
INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY
(2021)
Article
Food Science & Technology
Jinying Liang, Shiqi Guo, Mengxin Bai, Mengying Huang, Yupeng Qu, Ying Zhao, Yu Song
Summary: A unique micelle-liposome hybrid nanoparticle platform was designed for the combinatory administration of doxorubicin and Sphk2-siRNA for the treatment of multidrug-resistant breast cancer, reducing side effects and improving drug efficiency.
FOOD AND CHEMICAL TOXICOLOGY
(2023)
Review
Oncology
Preeti Gupta, Aaliya Taiyab, Afzal Hussain, Mohamed F. Alajmi, Asimul Islam, Md. Imtaiyaz Hassan
Summary: Cancer is a leading cause of global mortality, with SphK1 and its metabolite S1P being potential therapeutic targets due to their over-expression in various cancers and metabolic disorders. This review discusses the sphingolipid metabolism and the role of SphK isoforms in human malignancies, as well as the potential of SphK inhibitors in cancer therapy. It highlights the importance of sphingolipid metabolites in regulating physiological processes and the significance of the SphK/S1P signaling axis in human pathologies.
Article
Cell Biology
Guixin Zhu, Meenhard Herlyn, Xiaolu Yang
Summary: ERK1 and ERK2, the key mitogenic pathway in mammalian cells, are not only activated by MAPK/ERK kinase, but also modified by K63-linked polyubiquitin chains. TRIM15 and CYLD regulate ERK ubiquitination through different interactions and activities. K63-linked polyubiquitination enhances ERK interaction with and activation by MEK, providing a potential target for cancer therapy.
NATURE CELL BIOLOGY
(2021)
Article
Cell Biology
Wanting Shao, Melitta B. Koepke, Theresa Vilsmaier, Alaleh Zati Zehni, Mirjana Kessler, Sophie Sixou, Mariella Schneider, Nina Ditsch, Vincent Cavailles, Udo Jeschke
Summary: The cytoplasmic co-expression of RXR alpha and PPAR gamma in breast cancer patients is associated with shorter survival and tumor aggressiveness markers. This finding is clinically relevant for identifying high-risk breast cancer patients, especially those with early and node-negative disease.
Article
Biochemistry & Molecular Biology
Ilma Shakeel, Shama Khan, Sonam Roy, Fakhir Sherwani, Sheikh F. Ahmad, Sukhwinder Singh Sohal, Mohammad Afzal, Md Imtaiyaz Hassan
Summary: The signaling of SphK1 and S1P regulates various diseases, and this study explores the inhibitory potential and binding affinity of SphK1 with CA, SA, and MF. The compounds bind to SphK1 with high affinity and inhibit its kinase activity. These findings suggest the potential of designing novel anti-cancer therapeutics by targeting SphK1.
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
(2023)
Article
Biochemistry & Molecular Biology
Sonam Roy, Shama Khan, Deeba Shamim Jairajpuri, Afzal Hussain, Mohamed F. Alajmi, Asimul Islam, Suaib Luqman, Suhel Parvez, Md Imtaiyaz Hassan
Summary: Sphingosine kinase 1 (SphK1) and sphingosine-1-phosphate (S1P) signaling play crucial roles in regulating various diseases, especially in cancers such as breast, lung, colon, and hepatocellular carcinomas. Compounds like cinchonine and colcemid have high affinity for SphK1 and show potential in inhibiting its kinase activity.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2022)
Article
Oncology
Khanh T. Do, Bose Kochupurakkal, Sarah Kelland, Adrienne de Jonge, Jennifer Hedglin, Allison Powers, Nicholas Quinn, Courtney Gannon, Loan Vuong, Kalindi Parmar, Jean-Bernard Lazaro, Alan D. D'Andrea, Geoffrey I. Shapiro
Summary: The study aimed to enhance treatment sensitivity in BRCA-deficient cancers by combining CHK1 inhibitor and PARP inhibitor, showing preliminary clinical activity in high-grade serous ovarian cancer patients and effective intervention in DNA damage and replication stress.
CLINICAL CANCER RESEARCH
(2021)
Article
Oncology
Cheng-Fan Lee, Yu-An Chen, Elizabeth Hernandez, Rey-Chen Pong, Shihong Ma, Mia Hofstad, Payal Kapur, Haiyen Zhau, Leland W. K. Chung, Chih-Ho Lai, Ho Lin, Ming-Shyue Lee, Ganesh Raj, Jer-Tsong Hsieh
Summary: This study reveals the important role of SphK1 in NEPC development, providing a new target for the treatment of NEPC using SphK1 inhibitors.
CLINICAL AND TRANSLATIONAL MEDICINE
(2022)
Article
Cell Biology
Xin Peng, Xiaoli Liu, Wanshan Hu, Yanling Zhou, Lianlian Ouyang, Xintong Peng, Yao Long, Jingyue Sun, Tania Tao, Ling Chen, Ying Shi, Yongguang Tao, Desheng Xiao, Shuang Liu
Summary: In lung adenocarcinoma, overexpression of HOXC11 is associated with worse survival and is regulated by IKK alpha. HOXC11 promotes lung cancer progression by enhancing the expression of SPHK1 through directly binding to its promoter region.
CELL DEATH & DISEASE
(2023)
Article
Oncology
Yang Wu, Zheqi Li, Abdalla M. Wedn, Allison N. Casey, Daniel Brown, Shalini Rao, Soleilmane Omarjee, Jagmohan Hooda, Jason S. Carroll, Jason Gertz, Jennifer M. Atkinson, Adrian Lee, Steffi Oesterreich
Summary: Estrogen receptor alpha (ER/ESR1) mutations are common in endocrine resistant ER-positive breast cancer. Forkhead box A1 (FOXA1) plays a role in ER-chromatin interactions and endocrine response, but its role in ESR1-mutant breast cancer is unclear. This study shows that FOXA1 redistribution is associated with transcriptomic alterations caused by ESR1 mutations and suggests targeting the retinoid X receptor (RXR) pathway as a therapeutic strategy for breast tumors with ESR1 mutation.
MOLECULAR CANCER RESEARCH
(2023)