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Wang W, Li X, Wang H, Huang C, Zhu L, Wang H, Zhang W. CircDIAPH1 Promotes Liver Metastasis and Development of Colorectal Cancer by Initiation of CEACAM6 Expression. Mol Carcinog 2025; 64:897-910. [PMID: 39987565 DOI: 10.1002/mc.23896] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Revised: 01/25/2025] [Accepted: 02/10/2025] [Indexed: 02/25/2025]
Abstract
Liver metastasis is a critical factor influencing the 5-year survival rate in colorectal cancer (CRC). However, the biological function of most circRNAs in liver metastasis of CRC is still unknown. In this study, we identified differentially expressed circRNAs associated with liver metastasis (LM-DE-circRNAs). A total of 247 LM-DE-circRNAs were identified, and crucial signaling pathways, including the regulation of actin cytoskeleton, were significantly enriched, featuring six LM-DE-circRNAs. Notably, circDIAPH1 (hsa_circ_0074323), with the highest AUC value, emerged as a potential biomarker for CRC liver metastasis (CRLM). Functional assays following circDIAPH1 knockdown demonstrated induced apoptosis, suppressed proliferation, reduced metastasis, and invasion in CRC cell lines in vitro. The circDIAPH1 knockdown attenuated tumor growth in a cell-derived xenograft model. Furthermore, circDIAPH1 knockdown lessened the liver metastasis. Transcriptome profiling revealed that CEACAM6 was the most downregulated gene while circDIAPH1 was knocked down, and possesses high expression value in CRC. Most importantly, we found that circDIAPH1 recruited transcription factor FOXA1 to bind in the promoter region of CEACAM6 and initiated CEACAM6 expression. Additionally, the study identified the transcription factor BRD4 as a regulator of circDIAPH1 expression in CRC. In conclusion, this study reveals that circDIAPH1 recruits FOXA1 to initiate CEACAM6 expression, promoting liver metastasis and development of CRC.
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Affiliation(s)
- Wei Wang
- Department of Colorectal Surgery, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Xu Li
- Department of Colorectal Surgery, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Hantao Wang
- Department of Colorectal Surgery, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Cheng Huang
- Department of Colorectal Surgery, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Laicheng Zhu
- Department of Colorectal Surgery, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Hao Wang
- Department of Colorectal Surgery, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
| | - Wei Zhang
- Department of Colorectal Surgery, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai, China
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Boff MO, Xavier FAC, Diz FM, Gonçalves JB, Ferreira LM, Zambeli J, Pazzin DB, Previato TTR, Erwig HS, Gonçalves JIB, Bruzzo FTK, Marinowic D, da Costa JC, Zanirati G. mTORopathies in Epilepsy and Neurodevelopmental Disorders: The Future of Therapeutics and the Role of Gene Editing. Cells 2025; 14:662. [PMID: 40358185 PMCID: PMC12071303 DOI: 10.3390/cells14090662] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2025] [Revised: 02/06/2025] [Accepted: 02/06/2025] [Indexed: 05/15/2025] Open
Abstract
mTORopathies represent a group of neurodevelopmental disorders linked to dysregulated mTOR signaling, resulting in conditions such as tuberous sclerosis complex, focal cortical dysplasia, hemimegalencephaly, and Smith-Kingsmore Syndrome. These disorders often manifest with epilepsy, cognitive impairments, and, in some cases, structural brain anomalies. The mTOR pathway, a central regulator of cell growth and metabolism, plays a crucial role in brain development, where its hyperactivation leads to abnormal neuroplasticity, tumor formation, and heightened neuronal excitability. Current treatments primarily rely on mTOR inhibitors, such as rapamycin, which reduce seizure frequency and tumor size but fail to address underlying genetic causes. Advances in gene editing, particularly via CRISPR/Cas9, offer promising avenues for precision therapies targeting the genetic mutations driving mTORopathies. New delivery systems, including viral and non-viral vectors, aim to enhance the specificity and efficacy of these therapies, potentially transforming the management of these disorders. While gene editing holds curative potential, challenges remain concerning delivery, long-term safety, and ethical considerations. Continued research into mTOR mechanisms and innovative gene therapies may pave the way for transformative, personalized treatments for patients affected by these complex neurodevelopmental conditions.
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Affiliation(s)
- Marina Ottmann Boff
- Brain Institute of Rio Grande do Sul (BraIns), Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre 90610-000, RS, Brazil; (M.O.B.); (F.A.C.X.); (F.M.D.); (J.B.G.); (L.M.F.); (J.Z.); (D.B.P.); (T.T.R.P.); (H.S.E.); (J.I.B.G.); (F.T.K.B.); (D.M.); (J.C.d.C.)
- School of Medicine, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre 90619-900, RS, Brazil
| | - Fernando Antônio Costa Xavier
- Brain Institute of Rio Grande do Sul (BraIns), Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre 90610-000, RS, Brazil; (M.O.B.); (F.A.C.X.); (F.M.D.); (J.B.G.); (L.M.F.); (J.Z.); (D.B.P.); (T.T.R.P.); (H.S.E.); (J.I.B.G.); (F.T.K.B.); (D.M.); (J.C.d.C.)
- Graduate Program in Medicine and Health Sciences, School of Medicine, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre 90619-900, RS, Brazil
| | - Fernando Mendonça Diz
- Brain Institute of Rio Grande do Sul (BraIns), Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre 90610-000, RS, Brazil; (M.O.B.); (F.A.C.X.); (F.M.D.); (J.B.G.); (L.M.F.); (J.Z.); (D.B.P.); (T.T.R.P.); (H.S.E.); (J.I.B.G.); (F.T.K.B.); (D.M.); (J.C.d.C.)
| | - Júlia Budelon Gonçalves
- Brain Institute of Rio Grande do Sul (BraIns), Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre 90610-000, RS, Brazil; (M.O.B.); (F.A.C.X.); (F.M.D.); (J.B.G.); (L.M.F.); (J.Z.); (D.B.P.); (T.T.R.P.); (H.S.E.); (J.I.B.G.); (F.T.K.B.); (D.M.); (J.C.d.C.)
| | - Laura Meireles Ferreira
- Brain Institute of Rio Grande do Sul (BraIns), Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre 90610-000, RS, Brazil; (M.O.B.); (F.A.C.X.); (F.M.D.); (J.B.G.); (L.M.F.); (J.Z.); (D.B.P.); (T.T.R.P.); (H.S.E.); (J.I.B.G.); (F.T.K.B.); (D.M.); (J.C.d.C.)
- School of Medicine, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre 90619-900, RS, Brazil
| | - Jean Zambeli
- Brain Institute of Rio Grande do Sul (BraIns), Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre 90610-000, RS, Brazil; (M.O.B.); (F.A.C.X.); (F.M.D.); (J.B.G.); (L.M.F.); (J.Z.); (D.B.P.); (T.T.R.P.); (H.S.E.); (J.I.B.G.); (F.T.K.B.); (D.M.); (J.C.d.C.)
- School of Medicine, University of the Valley of the Rio dos Sinos (UNISINOS), São Leopoldo 93022-750, RS, Brazil
| | - Douglas Bottega Pazzin
- Brain Institute of Rio Grande do Sul (BraIns), Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre 90610-000, RS, Brazil; (M.O.B.); (F.A.C.X.); (F.M.D.); (J.B.G.); (L.M.F.); (J.Z.); (D.B.P.); (T.T.R.P.); (H.S.E.); (J.I.B.G.); (F.T.K.B.); (D.M.); (J.C.d.C.)
- Graduate Program in Pediatrics and Child Health, School of Medicine, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre 90619-900, RS, Brazil
| | - Thales Thor Ramos Previato
- Brain Institute of Rio Grande do Sul (BraIns), Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre 90610-000, RS, Brazil; (M.O.B.); (F.A.C.X.); (F.M.D.); (J.B.G.); (L.M.F.); (J.Z.); (D.B.P.); (T.T.R.P.); (H.S.E.); (J.I.B.G.); (F.T.K.B.); (D.M.); (J.C.d.C.)
- Graduate Program in Biomedical Gerontology, School of Medicine, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre 90619-900, RS, Brazil
| | - Helena Scartassini Erwig
- Brain Institute of Rio Grande do Sul (BraIns), Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre 90610-000, RS, Brazil; (M.O.B.); (F.A.C.X.); (F.M.D.); (J.B.G.); (L.M.F.); (J.Z.); (D.B.P.); (T.T.R.P.); (H.S.E.); (J.I.B.G.); (F.T.K.B.); (D.M.); (J.C.d.C.)
- School of Health and Life, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre 90619-900, RS, Brazil
| | - João Ismael Budelon Gonçalves
- Brain Institute of Rio Grande do Sul (BraIns), Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre 90610-000, RS, Brazil; (M.O.B.); (F.A.C.X.); (F.M.D.); (J.B.G.); (L.M.F.); (J.Z.); (D.B.P.); (T.T.R.P.); (H.S.E.); (J.I.B.G.); (F.T.K.B.); (D.M.); (J.C.d.C.)
| | - Fernanda Thays Konat Bruzzo
- Brain Institute of Rio Grande do Sul (BraIns), Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre 90610-000, RS, Brazil; (M.O.B.); (F.A.C.X.); (F.M.D.); (J.B.G.); (L.M.F.); (J.Z.); (D.B.P.); (T.T.R.P.); (H.S.E.); (J.I.B.G.); (F.T.K.B.); (D.M.); (J.C.d.C.)
| | - Daniel Marinowic
- Brain Institute of Rio Grande do Sul (BraIns), Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre 90610-000, RS, Brazil; (M.O.B.); (F.A.C.X.); (F.M.D.); (J.B.G.); (L.M.F.); (J.Z.); (D.B.P.); (T.T.R.P.); (H.S.E.); (J.I.B.G.); (F.T.K.B.); (D.M.); (J.C.d.C.)
- School of Health and Life, Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre 90619-900, RS, Brazil
| | - Jaderson Costa da Costa
- Brain Institute of Rio Grande do Sul (BraIns), Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre 90610-000, RS, Brazil; (M.O.B.); (F.A.C.X.); (F.M.D.); (J.B.G.); (L.M.F.); (J.Z.); (D.B.P.); (T.T.R.P.); (H.S.E.); (J.I.B.G.); (F.T.K.B.); (D.M.); (J.C.d.C.)
| | - Gabriele Zanirati
- Brain Institute of Rio Grande do Sul (BraIns), Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre 90610-000, RS, Brazil; (M.O.B.); (F.A.C.X.); (F.M.D.); (J.B.G.); (L.M.F.); (J.Z.); (D.B.P.); (T.T.R.P.); (H.S.E.); (J.I.B.G.); (F.T.K.B.); (D.M.); (J.C.d.C.)
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3
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Bian W, Yang J, Xia Y, Li Y, Cheng Y, Wu Y, Gan J, Zhong J. Megavirus baoshanense Mb0671 modulates host translation and increases viral fitness. Front Microbiol 2025; 16:1574090. [PMID: 40356658 PMCID: PMC12066439 DOI: 10.3389/fmicb.2025.1574090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2025] [Accepted: 04/14/2025] [Indexed: 05/15/2025] Open
Abstract
Amoeba giant viruses encode many translation-related proteins, but the function of these proteins remains obscure. In the current work, we studied the potential eukaryotic translation initiation factor 4A (eIF4A, Mb0671) encoded by Megavirus baoshanense, a member of the family Mimiviridae. The protein was shown to possesse ATPase activity and RNA-binding capacity, localize in the cytoplasm of infected cells, and present in mature virions. Interactome analysis showed that Mb0671 interacted primarily with ribosomal proteins and translation-related proteins. Specifically, Mb0671 was found to interact indirectly with host eIF4A, suggesting that it was associated with the translation apparatus. Proteomic analysis revealed that the protein profile of Acanthamoeba castellanii cells stably expressing Mb0671 was altered significantly compared to wild-type cells. The cellular proteins that were significantly upregulated included those in the pathways of spliceosome, amino acids biosynthesis, ribosome biogenesis, vesicular transportation, mTOR signaling pathway, etc. Both Mb0671 overexpression or siRNA-mediated reduction of its expression level significantly affected the synthesis of viral proteins. Furthermore, overexpressing Mb0671 accelerated cell growth and virus replication, whereas reduction of Mb0671 expression by siRNA delayed virus replication. These results suggested that Mb0671 altered cellular translation, possibly through its association with the host translation machinery, and played an important role in enhancing virus adaptability.
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Affiliation(s)
- Wenya Bian
- State Key Laboratory of Genetics and Development of Complex Phenotypes, Department of Microbiology and Immunology, School of Life Sciences, Fudan University, Shanghai, China
| | - Jie Yang
- State Key Laboratory of Genetics and Development of Complex Phenotypes, Department of Biochemistry and Biophysics, School of Life Sciences, Fudan University, Shanghai, China
| | - Yucheng Xia
- State Key Laboratory of Genetics and Development of Complex Phenotypes, Department of Microbiology and Immunology, School of Life Sciences, Fudan University, Shanghai, China
| | - Yun Li
- State Key Laboratory of Genetics and Development of Complex Phenotypes, Department of Microbiology and Immunology, School of Life Sciences, Fudan University, Shanghai, China
| | - Yanjin Cheng
- State Key Laboratory of Genetics and Development of Complex Phenotypes, Department of Microbiology and Immunology, School of Life Sciences, Fudan University, Shanghai, China
| | - Yuchen Wu
- State Key Laboratory of Genetics and Development of Complex Phenotypes, Department of Microbiology and Immunology, School of Life Sciences, Fudan University, Shanghai, China
| | - Jianhua Gan
- State Key Laboratory of Genetics and Development of Complex Phenotypes, Department of Biochemistry and Biophysics, School of Life Sciences, Fudan University, Shanghai, China
| | - Jiang Zhong
- State Key Laboratory of Genetics and Development of Complex Phenotypes, Department of Microbiology and Immunology, School of Life Sciences, Fudan University, Shanghai, China
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Peterson PP, Croog S, Choi Y, Sun S, Heitman J. STRIPAK complex defects result in pseudosexual reproduction in Cryptococcus neoformans. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.04.08.647827. [PMID: 40297506 PMCID: PMC12036433 DOI: 10.1101/2025.04.08.647827] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/30/2025]
Abstract
STRIPAK is an evolutionarily conserved signaling complex that coordinates diverse cellular processes across fungi and animals. In the human fungal pathogen Cryptococcus neoformans , STRIPAK was recently shown to play critical roles in maintaining genome stability and controlling both sexual and asexual development. In Cryptococcus , sexual reproduction is closely linked to virulence, and our findings demonstrate that the STRIPAK complex plays key roles in both processes. Here, we further investigate the specific roles of the STRIPAK catalytic subunit Pph22 and its regulatory partner Far8 during sexual development. We show that while pph22 Δ mutants are defective in α- a sexual reproduction, exhibiting impaired meiotic progression and a failure to produce viable spores, the deletion of PPH22 resulted in exclusive pseudosexual reproduction, with progeny inheriting nuclear genomes solely from the wild-type parent. Overexpression of PPG1 , a related phosphatase, rescued growth and developmental defects in pph22 Δ mutants, and restored the preference for α- a sexual reproduction over pseudosexual reproduction during mating, suggesting functional redundancy within the STRIPAK signaling network. Furthermore, deletion of FAR8 , another component of the STRIPAK complex, also led to a high rate of pseudosexual reproduction during α- a sexual mating, reinforcing the role of STRIPAK in modulating reproductive modes in C. neoformans , possibly through regulating nuclear inheritance and meiotic progression. Together, these findings highlight the distinct contributions of STRIPAK to sexual reproduction in C. neoformans and suggest that disruptions of this complex affect genome integrity and inheritance mechanisms, with broader implications for fungal adaptation and pathogenesis.
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Khayatan D, Razavi SM, Arab ZN, Nasoori H, Fouladi A, Pasha AVK, Butler AE, Karav S, Momtaz S, Abdolghaffari AH, Sahebkar A. Targeting mTOR with curcumin: therapeutic implications for complex diseases. Inflammopharmacology 2025; 33:1583-1616. [PMID: 39955697 DOI: 10.1007/s10787-025-01643-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Accepted: 10/16/2024] [Indexed: 02/17/2025]
Abstract
The mammalian target of rapamycin (mTOR) is a crucial enzyme in regulating multiple signaling pathways in the body, including autophagy, proliferation and apoptosis. Disruption of these mTOR signaling pathways can lead to an array of abnormalities and trigger disease processes, examples being neurodegenerative conditions, cancer, obesity and diabetes. Under conditions of oxidative stress, mTOR can regulate apoptosis and autophagy, with tissue repair being favored under such circumstances. Moreover, the correlation between mTOR and other signaling pathways could play a pivotal role in the pathophysiology of numerous disorders. mTOR has a tight connection with NF-κB, Akt, PI3K, MAPK, GSK-3β, Nrf2/HO-1, JAK/STAT, CREB/BDNF, and ERK1/2 pathways, which together could play significant roles in the regulation of inflammation, apoptosis, cell survival, and oxidative stress in different body organs. Research suggests that inhibiting mTOR could be beneficial in treating metabolic, neurological and cardiovascular conditions, as well as potentially extending life expectancy. Therefore, identifying new chemicals and agents that can modulate the mTOR signaling pathway holds promise for treating and preventing these disorders. Curcumin is one such agent that has demonstrated regulatory effects on the mTOR pathway, making it an exciting alternative for reducing complications associated with complex diseases by targeting mTOR. This review aims to examine the potential of curcumin in modulating the mTOR signaling pathway and its therapeutic implications.
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Affiliation(s)
- Danial Khayatan
- Department of Toxicology & Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- GI Pharmacology Interest Group (GPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Seyed Mehrad Razavi
- Department of Toxicology & Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- GI Pharmacology Interest Group (GPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Zahra Najafi Arab
- Department of Toxicology & Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- GI Pharmacology Interest Group (GPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Hadis Nasoori
- Department of Toxicology & Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- GI Pharmacology Interest Group (GPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Abtin Fouladi
- GI Pharmacology Interest Group (GPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Aytak Vahdat Khajeh Pasha
- Department of Toxicology & Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- GI Pharmacology Interest Group (GPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Alexandra E Butler
- Research Department, Royal College of Surgeons in Ireland, Bahrain, Adliya, Bahrain
| | - Sercan Karav
- Department of Molecular Biology and Genetics, Canakkale Onsekiz Mart University, Canakkale, 17100, Turkey
| | - Saeideh Momtaz
- GI Pharmacology Interest Group (GPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
- Medicinal Plants Research Center, Institute of Medicinal Plants, ACECR, Karaj, Iran
- Department of Toxicology and Pharmacology, School of Pharmacy, and Toxicology and Diseases Group, Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran
| | - Amir Hossein Abdolghaffari
- Department of Toxicology & Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
- GI Pharmacology Interest Group (GPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran.
| | - Amirhossein Sahebkar
- Center for Global Health Research, Saveetha Medical College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India.
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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Zhao X, Lai H, Li G, Qin Y, Chen R, Labrie M, Stommel JM, Mills GB, Ma D, Gao Q, Fang Y. Rictor orchestrates β-catenin/FOXO balance by maintaining redox homeostasis during development of ovarian cancer. Oncogene 2025:10.1038/s41388-025-03351-x. [PMID: 40133477 DOI: 10.1038/s41388-025-03351-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Revised: 02/14/2025] [Accepted: 03/11/2025] [Indexed: 03/27/2025]
Abstract
Rictor/mTORC2 has been demonstrated to have important roles in cancer development and progression in a number of solid and hematologic malignancies. However, little is known about the role of Rictor/mTORC2 in ovarian cancer pathophysiology. Herein, using conditional Rictor knockout mice, we were able to demonstrate that Rictor deletion disrupted glutathione metabolism through AKT/Nrf2 signaling pathway and induced intracellular oxidative stress during the malignant transformation of Kras/Pten-mutant ovarian surface epithelial cells. Elevated reactive oxygen species and activated FOXO3a in Rictor-deleted cells strikingly shifts the functional interaction of β-catenin from TCF to FOXO3a, which strongly inhibits classical Wnt/β-catenin signaling. Our findings emphasize a pivotal role for Rictor in orchestrating crosstalk between the PI3K/AKT and Wnt/β-catenin signaling in the development of ovarian cancer. Illustration of Rictor/mTORC2 in promoting tumor onset by regulating glutathione metabolism and mediating oncogenic signaling.
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Affiliation(s)
- Xuejiao Zhao
- National Clinical Research Center for Obstetrics and Gynaecology, Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Gynaecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Huiling Lai
- Department of Gynecology, the Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Guannan Li
- National Clinical Research Center for Obstetrics and Gynaecology, Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Gynaecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yu Qin
- National Clinical Research Center for Obstetrics and Gynaecology, Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Gynaecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ruqi Chen
- National Clinical Research Center for Obstetrics and Gynaecology, Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Gynaecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Marilyne Labrie
- Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada
| | - Jayne M Stommel
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA
| | - Gordon B Mills
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA
- Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, OR, USA
| | - Ding Ma
- National Clinical Research Center for Obstetrics and Gynaecology, Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
- Department of Gynaecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Qinglei Gao
- National Clinical Research Center for Obstetrics and Gynaecology, Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
- Department of Gynaecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Yong Fang
- National Clinical Research Center for Obstetrics and Gynaecology, Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
- Department of Gynaecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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7
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Adams-Brown SE, Reid KZ. The Central FacilitaTOR: Coordinating Transcription and Translation in Eukaryotes. Int J Mol Sci 2025; 26:2845. [PMID: 40243440 PMCID: PMC11989106 DOI: 10.3390/ijms26072845] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2025] [Revised: 03/11/2025] [Accepted: 03/17/2025] [Indexed: 04/18/2025] Open
Abstract
One of the biggest challenges to eukaryotic gene expression is coordinating transcription in the nucleus and protein synthesis in the cytoplasm. However, little is known about how these major steps in gene expression are connected. The Target of Rapamycin (TOR) signaling pathway is crucial in connecting these critical phases of gene expression. Highly conserved among eukaryotic cells, TOR regulates growth, metabolism, and cellular equilibrium in response to changes in nutrients, energy levels, and stress conditions. This review examines the extensive role of TOR in gene expression regulation. We highlight how TOR is involved in phosphorylation, remodeling chromatin structure, and managing the factors that facilitate transcription and translation. Furthermore, the critical functions of TOR extend to processing RNA, assembling RNA-protein complexes, and managing their export from the nucleus, demonstrating its wide-reaching impact throughout the cell. Our discussion emphasizes the integral roles of TOR in bridging the processes of transcription and translation and explores how it orchestrates these complex cellular processes.
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Affiliation(s)
| | - Ke Zhang Reid
- Department of Biology, Wake Forest University, Winston-Salem, NC 27109, USA
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Song Y, Wang F, Luo H, Hu H, Pang Y, Xu K, Zhang X. Rapamycin protects glucocorticoid-induced glaucoma model mice against trabecular meshwork fibrosis by suppressing mTORC1/2 signaling. Eur J Pharmacol 2025; 990:177269. [PMID: 39805488 DOI: 10.1016/j.ejphar.2025.177269] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Revised: 01/08/2025] [Accepted: 01/09/2025] [Indexed: 01/16/2025]
Abstract
Systemic or local use of glucocorticoids (GCs) can induce pathological elevation of intraocular pressure (IOP), potentially leading to permanent visual loss. Previous studies have demonstrated that rapamycin (Rapa) inhibits the activation of retinal glial cells (RGC) and the production of neuroinflammation, achieving neuroprotective goals. However, there has been little research on the effect of Rapa on the trabecular meshwork (TM). This study aimed to investigate the protective effect and potential mechanism of Rapa in a glucocorticoid-induced glaucoma (GIG) model. Our findings indicate that Rapa significantly inhibited the IOP increase induced by dexamethasone acetate (Dex-Ac) and improved TM fibrosis and RGC damage. In cultured human trabecular meshwork cells (HTMCs) treated with dexamethasone (Dex) and Rapa under different conditions revealed that Rapa inhibits Dex-induced HTMC fibrosis and cytoskeletal changes. This effect may result from the specific suppression of the mechanistic target of rapamycin complex 1 (mTORC1) pathway by Rapa, which reduces abnormal extracellular matrix (ECM) deposition. Alternatively, the improvement in cytoskeleton entanglement might be due to the inhibition of the mechanistic target of rapamycin complex 2 (mTORC2) pathway. These two potential mechanisms may collectively contribute to the protective effects of Rapa in GIG. This study provides a new theoretical basis for using of Rapa in the treatment of GIG.
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Affiliation(s)
- Yuning Song
- Affiliated Eye Hospital of Nanchang University, Jiangxi Medical College, Nanchang University, Jiangxi Research Institute of Ophthalmology & Visual Science, Jiangxi Provincial Key Laboratory for Ophthalmology, Jiangxi Clinical Research Center for Ophthalmic Disease, Nanchang, China
| | - Feifei Wang
- Affiliated Eye Hospital of Nanchang University, Jiangxi Medical College, Nanchang University, Jiangxi Research Institute of Ophthalmology & Visual Science, Jiangxi Provincial Key Laboratory for Ophthalmology, Jiangxi Clinical Research Center for Ophthalmic Disease, Nanchang, China; Department of Ophthalmology, The Second Affiliated Hospital of Nanchang University, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Hongdou Luo
- Affiliated Eye Hospital of Nanchang University, Jiangxi Medical College, Nanchang University, Jiangxi Research Institute of Ophthalmology & Visual Science, Jiangxi Provincial Key Laboratory for Ophthalmology, Jiangxi Clinical Research Center for Ophthalmic Disease, Nanchang, China
| | - Haijian Hu
- Affiliated Eye Hospital of Nanchang University, Jiangxi Medical College, Nanchang University, Jiangxi Research Institute of Ophthalmology & Visual Science, Jiangxi Provincial Key Laboratory for Ophthalmology, Jiangxi Clinical Research Center for Ophthalmic Disease, Nanchang, China
| | - Yulian Pang
- Affiliated Eye Hospital of Nanchang University, Jiangxi Medical College, Nanchang University, Jiangxi Research Institute of Ophthalmology & Visual Science, Jiangxi Provincial Key Laboratory for Ophthalmology, Jiangxi Clinical Research Center for Ophthalmic Disease, Nanchang, China
| | - Ke Xu
- Affiliated Eye Hospital of Nanchang University, Jiangxi Medical College, Nanchang University, Jiangxi Research Institute of Ophthalmology & Visual Science, Jiangxi Provincial Key Laboratory for Ophthalmology, Jiangxi Clinical Research Center for Ophthalmic Disease, Nanchang, China
| | - Xu Zhang
- Affiliated Eye Hospital of Nanchang University, Jiangxi Medical College, Nanchang University, Jiangxi Research Institute of Ophthalmology & Visual Science, Jiangxi Provincial Key Laboratory for Ophthalmology, Jiangxi Clinical Research Center for Ophthalmic Disease, Nanchang, China.
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9
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Shi J, Liu X, Jiao Y, Tian J, An J, Zou G, Zhuo L. mTOR pathway: A key player in diabetic nephropathy progression and therapeutic targets. Genes Dis 2025; 12:101260. [PMID: 39717716 PMCID: PMC11665407 DOI: 10.1016/j.gendis.2024.101260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Revised: 01/26/2024] [Accepted: 02/21/2024] [Indexed: 12/25/2024] Open
Abstract
Diabetic nephropathy is a prevalent complication of diabetes and stands as the primary contributor to end-stage renal disease. The global prevalence of diabetic nephropathy is on the rise, however, due to its intricate pathogenesis, there is currently an absence of efficacious treatments to enhance renal prognosis in affected patients. The mammalian target of rapamycin (mTOR), a serine/threonine protease, assumes a pivotal role in cellular division, survival, apoptosis delay, and angiogenesis. It is implicated in diverse signaling pathways and has been observed to partake in the progression of diabetic nephropathy by inhibiting autophagy, promoting inflammation, and increasing oxidative stress. In this academic review, we have consolidated the understanding of the pathological mechanisms associated with four distinct resident renal cell types (podocytes, glomerular mesangial cells, renal tubular epithelial cells, and glomerular endothelial cells), as well as macrophages and T lymphocytes, within a diabetic environment. Additionally, we highlight the research progress in the treatment of diabetic nephropathy with drugs and various molecules interfering with the mTOR signaling pathway, providing a theoretical reference for the treatment and prevention of diabetic nephropathy.
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Affiliation(s)
- Jingxuan Shi
- Department of Nephrology, China-Japan Friendship Hospital, Beijing 100029, China
- China-Japan Friendship Institute of Clinical Medical Sciences, Beijing 100029, China
| | - Xinze Liu
- Beijing University of Chinese Medicine China-Japan Friendship Clinical Medical College, Beijing 100029, China
| | - Yuanyuan Jiao
- Department of Nephrology, Fuwai Hospital, Chinese Academy of Medical Science, Beijing 100037, China
| | - Jingwei Tian
- Department of Nephrology, Beijing Sixth Hospital, Beijing 100007, China
- Capital Medical University China-Japan Friendship School of Clinical Medicine, Beijing 100029, China
| | - Jiaqi An
- Department of Nephrology, China-Japan Friendship Hospital, Beijing 100029, China
- China-Japan Friendship Clinic Medical College, Peking University, Beijing 100191, China
| | - Guming Zou
- Department of Nephrology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Li Zhuo
- Department of Nephrology, China-Japan Friendship Hospital, Beijing 100029, China
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10
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Lee K, Kim HJ, Kim JE, Elina KC, Kim S, Park YS, Kim HK. Combination treatment with rapamycin and glucocorticoid protects the death of mesostriatal dopaminergic neurons in animal model of Parkinson's disease. Pharmacol Biochem Behav 2025; 248:173966. [PMID: 39904116 DOI: 10.1016/j.pbb.2025.173966] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Revised: 01/24/2025] [Accepted: 01/30/2025] [Indexed: 02/06/2025]
Abstract
Glucocorticoids have been used to treat inflammatory diseases because of their potent anti-inflammatory and immunosuppressive actions. However, chronic use of high levels of glucocorticoids causes several adverse effects, limiting their clinical utility. Here, we explored the therapeutic potential of a combination treatment involving reduced concentrations of rapamycin, an autophagy activator and immunosuppressant, and glucocorticoids in an animal model of Parkinson's disease (PD). In vitro experiments with the SH-SY5Y cell line revealed that 10 μM rapamycin significantly increased the survival rate of cells treated with 6-hydroxydopamine to induce cell death, while both dexamethasone and prednisone at 50 μM exhibited an evident increase in survival rates. The combination treatment with reduced concentrations (rapamycin: 5 μM, dexamethasone: 25 μM) showed a more effective recovery in survival than singular treatments with high concentrations of rapamycin, prednisone, or dexamethasone. Propidium iodide-staining confirmed the efficacy of the combination treatment. This treatment did not significantly alter forkhead box O3a (FOXO3a)-triggered apoptosis and autophagic flux but upregulated the expression of the anti-apoptotic protein B-cell lymphoma 2, while B-cell lymphoma-extra-large showed no significant change. In vivo experiments using a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD animal model revealed that the combination treatment effectively mitigated defects in motor function. The combination treatment completely blocked the loss of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra pars compacta and partially prevented the reduction of TH-positive fibers in the striatum caused by the MPTP treatment. It also reduced the microglial levels caused by the MPTP treatment. Although not significant, it demonstrated an increase in survival rates of MPTP-induced PD model mice. In conclusion, the combination treatment with reduced concentrations of rapamycin and glucocorticoids may serve as potential therapy for PD, albeit further research and clinical trials are warranted to validate its efficacy and safety.
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Affiliation(s)
- Kina Lee
- Graduate Program in Neuroscience, Department of Medicine and Microbiology, Chungbuk National University, Cheongju, Republic of Korea
| | - Hee Jeong Kim
- Graduate Program in Neuroscience, Department of Medicine and Microbiology, Chungbuk National University, Cheongju, Republic of Korea
| | - Jeong Eun Kim
- Graduate Program in Neuroscience, Department of Medicine and Microbiology, Chungbuk National University, Cheongju, Republic of Korea
| | - K C Elina
- Graduate Program in Neuroscience, Department of Neurosurgery, Chungbuk National University, Cheongju, Republic of Korea
| | - Sangjune Kim
- Department of Biology, Chungbuk National University, Cheongju, Republic of Korea
| | - Young Seok Park
- Graduate Program in Neuroscience, Department of Neurosurgery, Chungbuk National University, Cheongju, Republic of Korea
| | - Hyong Kyu Kim
- Graduate Program in Neuroscience, Department of Medicine and Microbiology, Chungbuk National University, Cheongju, Republic of Korea.
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11
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Patel SS, Cook RS, Lo JH, Cherry FK, Hoogenboezem EN, Yu F, Francini N, Cassidy NT, McCune JT, Gbur EF, Messier L, Dean TA, Wilson KL, Brantley-Sieders DM, Duvall CL. Induction of Triple-Negative Breast Cancer Cell Death and Chemosensitivity Using mTORC2-Directed RNAi Nanomedicine. CANCER RESEARCH COMMUNICATIONS 2025; 5:458-476. [PMID: 40019775 PMCID: PMC11921867 DOI: 10.1158/2767-9764.crc-24-0261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Revised: 11/13/2024] [Accepted: 02/26/2025] [Indexed: 03/01/2025]
Abstract
SIGNIFICANCE We identified an mTORC2/Rictor-directed RNAi nanomedicine that cooperates with chemotherapy to enhance in vivo tumor cell killing in PI3K-active TNBCs.
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Affiliation(s)
- Shrusti S. Patel
- Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee
| | - Rebecca S. Cook
- Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee
| | - Justin H. Lo
- Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Fiona K. Cherry
- Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee
| | - Ella N. Hoogenboezem
- Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee
| | - Fang Yu
- Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee
| | - Nora Francini
- Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee
| | - Nina T. Cassidy
- Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee
| | - Joshua T. McCune
- Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee
| | - Eva F. Gbur
- Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee
| | - Lisa Messier
- Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee
| | - Thomas A. Dean
- Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee
| | - Kalin L. Wilson
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | | | - Craig L. Duvall
- Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee
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12
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Leo IR, Kunold E, Audrey A, Tampere M, Eirich J, Lehtiö J, Jafari R. Functional proteoform group deconvolution reveals a broader spectrum of ibrutinib off-targets. Nat Commun 2025; 16:1948. [PMID: 40000607 PMCID: PMC11862126 DOI: 10.1038/s41467-024-54654-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Accepted: 11/13/2024] [Indexed: 02/27/2025] Open
Abstract
Proteome-wide profiling has revealed that targeted drugs can have complex protein interaction landscapes. However, it's a challenge to profile drug targets while systematically accounting for the dynamic protein variations that produce populations of multiple proteoforms. We address this problem by combining thermal proteome profiling (TPP) with functional proteoform group detection to refine the target landscape of ibrutinib. In addition to known targets, we implicate additional specific functional proteoform groups linking ibrutinib to mechanisms in immunomodulation and cellular processes like Golgi trafficking, endosomal trafficking, and glycosylation. Further, we identify variability in functional proteoform group profiles in a CLL cohort, linked to treatment status and ex vivo response and resistance. This offers deeper insights into the impacts of functional proteoform groups in a clinical treatment setting and suggests complex biological effects linked to off-target engagement. These results provide a framework for interpreting clinically observed off-target processes and adverse events, highlighting the importance of functional proteoform group-level deconvolution in understanding drug interactions and their functional impacts with potential applications in precision medicine.
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Affiliation(s)
- Isabelle Rose Leo
- Clinical Proteomics Mass Spectrometry, Department of Oncology-Pathology, Karolinska Institutet, Science for Life Laboratory, Solna, Sweden
| | - Elena Kunold
- Clinical Proteomics Mass Spectrometry, Department of Oncology-Pathology, Karolinska Institutet, Science for Life Laboratory, Solna, Sweden
- Evotec International GmbH, München, Germany
| | - Anastasia Audrey
- Department of Medical Oncology, University Medical Center Groningen, Groningen, the Netherlands
| | - Marianna Tampere
- Precision Cancer Medicine, Department of Oncology-Pathology, Karolinska Institutet, Science for Life Laboratory, Solna, Sweden
| | - Jürgen Eirich
- Institute of Plant Biology and Biotechnology, University of Münster, Münster, Germany
| | - Janne Lehtiö
- Clinical Proteomics Mass Spectrometry, Department of Oncology-Pathology, Karolinska Institutet, Science for Life Laboratory, Solna, Sweden
| | - Rozbeh Jafari
- Clinical Proteomics Mass Spectrometry, Department of Oncology-Pathology, Karolinska Institutet, Science for Life Laboratory, Solna, Sweden.
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13
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Liu H, Wang S, Wang J, Guo X, Song Y, Fu K, Gao Z, Liu D, He W, Yang LL. Energy metabolism in health and diseases. Signal Transduct Target Ther 2025; 10:69. [PMID: 39966374 PMCID: PMC11836267 DOI: 10.1038/s41392-025-02141-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Revised: 11/08/2024] [Accepted: 12/25/2024] [Indexed: 02/20/2025] Open
Abstract
Energy metabolism is indispensable for sustaining physiological functions in living organisms and assumes a pivotal role across physiological and pathological conditions. This review provides an extensive overview of advancements in energy metabolism research, elucidating critical pathways such as glycolysis, oxidative phosphorylation, fatty acid metabolism, and amino acid metabolism, along with their intricate regulatory mechanisms. The homeostatic balance of these processes is crucial; however, in pathological states such as neurodegenerative diseases, autoimmune disorders, and cancer, extensive metabolic reprogramming occurs, resulting in impaired glucose metabolism and mitochondrial dysfunction, which accelerate disease progression. Recent investigations into key regulatory pathways, including mechanistic target of rapamycin, sirtuins, and adenosine monophosphate-activated protein kinase, have considerably deepened our understanding of metabolic dysregulation and opened new avenues for therapeutic innovation. Emerging technologies, such as fluorescent probes, nano-biomaterials, and metabolomic analyses, promise substantial improvements in diagnostic precision. This review critically examines recent advancements and ongoing challenges in metabolism research, emphasizing its potential for precision diagnostics and personalized therapeutic interventions. Future studies should prioritize unraveling the regulatory mechanisms of energy metabolism and the dynamics of intercellular energy interactions. Integrating cutting-edge gene-editing technologies and multi-omics approaches, the development of multi-target pharmaceuticals in synergy with existing therapies such as immunotherapy and dietary interventions could enhance therapeutic efficacy. Personalized metabolic analysis is indispensable for crafting tailored treatment protocols, ultimately providing more accurate medical solutions for patients. This review aims to deepen the understanding and improve the application of energy metabolism to drive innovative diagnostic and therapeutic strategies.
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Affiliation(s)
- Hui Liu
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Shuo Wang
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jianhua Wang
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xin Guo
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yujing Song
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Kun Fu
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhenjie Gao
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Danfeng Liu
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
| | - Wei He
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
| | - Lei-Lei Yang
- Department of Stomatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
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14
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Wang J, Huang Y, Wang Z, Liu J, Liu Z, Yang J, He Z. The mTOR Signaling Pathway: Key Regulator and Therapeutic Target for Heart Disease. Biomedicines 2025; 13:397. [PMID: 40002810 PMCID: PMC11853667 DOI: 10.3390/biomedicines13020397] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2024] [Revised: 01/25/2025] [Accepted: 02/04/2025] [Indexed: 02/27/2025] Open
Abstract
Heart disease, including myocardial infarction, heart failure, cardiac hypertrophy, and cardiomyopathy, remains a leading cause of mortality worldwide. The mammalian target of rapamycin (mTOR) is a centrally regulated kinase that governs key cellular processes, including growth, proliferation, metabolism, and survival. Notably, mTOR plays a pivotal role in cardiovascular health and disease, particularly in the onset and progression of cardiac conditions. In this review, we discuss mTOR's structure and function as well as the regulatory mechanisms of its associated signaling pathways. We focus on the molecular mechanisms by which mTOR signaling regulates cardiac diseases and the potential of mTOR inhibitors and related regulatory drugs in preventing these conditions. We conclude that the mTOR signaling pathway is a promising therapeutic target for heart disease.
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Affiliation(s)
- Jieyu Wang
- Department of Basic Medicine, School of Medicine, Hunan Normal University, Changsha 410013, China; (J.W.); (Y.H.); (Z.W.); (J.L.)
- The Key Laboratory of Model Animal and Stem Cell Biology in Hunan Province, Hunan Normal University, Changsha 410013, China
| | - Yuxuan Huang
- Department of Basic Medicine, School of Medicine, Hunan Normal University, Changsha 410013, China; (J.W.); (Y.H.); (Z.W.); (J.L.)
- The Key Laboratory of Model Animal and Stem Cell Biology in Hunan Province, Hunan Normal University, Changsha 410013, China
| | - Zhaoxia Wang
- Department of Basic Medicine, School of Medicine, Hunan Normal University, Changsha 410013, China; (J.W.); (Y.H.); (Z.W.); (J.L.)
- The Key Laboratory of Model Animal and Stem Cell Biology in Hunan Province, Hunan Normal University, Changsha 410013, China
| | - Jing Liu
- Department of Basic Medicine, School of Medicine, Hunan Normal University, Changsha 410013, China; (J.W.); (Y.H.); (Z.W.); (J.L.)
- The Key Laboratory of Model Animal and Stem Cell Biology in Hunan Province, Hunan Normal University, Changsha 410013, China
| | - Zhijian Liu
- Department of Anesthesiology, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya, School of Medicine, Central South University, Changsha 410013, China;
| | - Jinfeng Yang
- Department of Anesthesiology, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya, School of Medicine, Central South University, Changsha 410013, China;
| | - Zuping He
- Department of Basic Medicine, School of Medicine, Hunan Normal University, Changsha 410013, China; (J.W.); (Y.H.); (Z.W.); (J.L.)
- The Key Laboratory of Model Animal and Stem Cell Biology in Hunan Province, Hunan Normal University, Changsha 410013, China
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15
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Moloney PB, Delanty N. An overview of the value of mTOR inhibitors to the treatment of epilepsy: the evidence to date. Expert Rev Neurother 2025:1-17. [PMID: 39903448 DOI: 10.1080/14737175.2025.2462280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 01/30/2025] [Accepted: 01/30/2025] [Indexed: 02/06/2025]
Abstract
INTRODUCTION Dysregulated mechanistic target of rapamycin (mTOR) activity is implicated in seizure development in epilepsies caused by variants in mTOR pathway genes. Sirolimus and everolimus, allosteric mTOR inhibitors, are widely used in transplant medicine and oncology. Everolimus is approved for treating seizures in tuberous sclerosis complex (TSC), the prototype mTORopathy. Emerging evidence suggests that mTOR inhibitors could also be effective in other mTORopathies, such as DEPDC5-related epilepsy and focal cortical dysplasia type 2 (FCD2). AREAS COVERED This narrative review summarizes key regulatory proteins in the mTOR cascade and outlines epilepsy syndromes linked to variants in genes encoding these proteins, particularly TSC, GATOR1-related epilepsies, and FCD2. It discusses the clinical pharmacology of mTOR inhibitors and the evidence supporting their efficacy as antiseizure medications (ASM) in mTORopathies. Lastly, potential benefits of next-generation mTOR inhibitors for CNS indications are evaluated. EXPERT OPINION The therapeutic benefits of mTOR inhibitors in TSC are well-established, but their value in other mTORopathies remains uncertain. Despite targeting the underlying disease biology, their efficacy in TSC is not significantly different from other ASM, likely due in part to pharmacokinetic constraints. Next-generation mTOR inhibitors that address these limitations may offer improved response rates, but they are in the preclinical development phase.
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Affiliation(s)
- Patrick B Moloney
- Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, University College London, London, UK
- Department of Epilepsy, Chalfont Centre for Epilepsy, Chalfont St Peter, UK
| | - Norman Delanty
- Department of Neurology, Beaumont Hospital, Dublin, Ireland
- School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland
- Research Ireland FutureNeuro Centre, Dublin, Ireland
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16
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Han Z, Yan G, Jousma J, Nukala SB, Amiri M, Kiniry S, Tabatabaei N, Kwon Y, Zhang S, Rehman J, Pinho S, Ong SB, Baranov PV, Tahmasebi S, Ong SG. Translational regulation of SND1 governs endothelial homeostasis during stress. J Clin Invest 2025; 135:e168730. [PMID: 39895626 PMCID: PMC11785924 DOI: 10.1172/jci168730] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Accepted: 11/22/2024] [Indexed: 02/04/2025] Open
Abstract
Translational control shapes the proteome and is particularly important in regulating gene expression under stress. A key source of endothelial stress is treatment with tyrosine kinase inhibitors (TKIs), which lowers cancer mortality but increases cardiovascular mortality. Using a human induced pluripotent stem cell-derived endothelial cell (hiPSC-EC) model of sunitinib-induced vascular dysfunction combined with ribosome profiling, we assessed the role of translational control in hiPSC-ECs in response to stress. We identified staphylococcal nuclease and tudor domain-containing protein 1 (SND1) as a sunitinib-dependent translationally repressed gene. SND1 translational repression was mediated by the mTORC1/4E-BP1 pathway. SND1 inhibition led to endothelial dysfunction, whereas SND1 OE protected against sunitinib-induced endothelial dysfunction. Mechanistically, SND1 transcriptionally regulated UBE2N, an E2-conjugating enzyme that mediates K63-linked ubiquitination. UBE2N along with the E3 ligases RNF8 and RNF168 regulated the DNA damage repair response pathway to mitigate the deleterious effects of sunitinib. In silico analysis of FDA-approved drugs led to the identification of an ACE inhibitor, ramipril, that protected against sunitinib-induced vascular dysfunction in vitro and in vivo, all while preserving the efficacy of cancer therapy. Our study established a central role for translational control of SND1 in sunitinib-induced endothelial dysfunction that could potentially be therapeutically targeted to reduce sunitinib-induced vascular toxicity.
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Affiliation(s)
- Zhenbo Han
- Department of Pharmacology & Regenerative Medicine, University of Illinois College of Medicine, Chicago, Illinois, USA
| | - Gege Yan
- Department of Pharmacology & Regenerative Medicine, University of Illinois College of Medicine, Chicago, Illinois, USA
| | - Jordan Jousma
- Department of Pharmacology & Regenerative Medicine, University of Illinois College of Medicine, Chicago, Illinois, USA
| | - Sarath Babu Nukala
- Department of Pharmacology & Regenerative Medicine, University of Illinois College of Medicine, Chicago, Illinois, USA
| | - Mehdi Amiri
- Department of Biochemistry, McGill University, Montreal, Quebec, Canada
| | - Stephen Kiniry
- School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland
| | - Negar Tabatabaei
- Department of Pharmacology & Regenerative Medicine, University of Illinois College of Medicine, Chicago, Illinois, USA
| | - Youjeong Kwon
- Department of Pharmacology & Regenerative Medicine, University of Illinois College of Medicine, Chicago, Illinois, USA
| | - Sen Zhang
- Department of Pharmacology & Regenerative Medicine, University of Illinois College of Medicine, Chicago, Illinois, USA
| | - Jalees Rehman
- Department of Pharmacology & Regenerative Medicine, University of Illinois College of Medicine, Chicago, Illinois, USA
- University of Illinois Cancer Center, Chicago, Illinois, USA
| | - Sandra Pinho
- Department of Pharmacology & Regenerative Medicine, University of Illinois College of Medicine, Chicago, Illinois, USA
- University of Illinois Cancer Center, Chicago, Illinois, USA
| | - Sang-Bing Ong
- Department of Medicine and Therapeutics, Faculty of Medicine, Chinese University of Hong Kong (CUHK), Hong Kong SAR, China
- Centre for Cardiovascular Genomics and Medicine (CCGM), Lui Che Woo Institute of Innovative Medicine, CUHK, Hong Kong SAR, China
- Hong Kong Hub of Pediatric Excellence (HK HOPE), Hong Kong Children’s Hospital (HKCH), Hong Kong SAR, China
- Kunming Institute of Zoology — The Chinese University of Hong Kong (KIZ-CUHK) Joint Laboratory of Bioresources and Molecular Research of Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China
| | - Pavel V. Baranov
- School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland
| | - Soroush Tahmasebi
- Department of Pharmacology & Regenerative Medicine, University of Illinois College of Medicine, Chicago, Illinois, USA
- University of Illinois Cancer Center, Chicago, Illinois, USA
| | - Sang-Ging Ong
- Department of Pharmacology & Regenerative Medicine, University of Illinois College of Medicine, Chicago, Illinois, USA
- Division of Cardiology, Department of Medicine, University of Illinois College of Medicine, Chicago, Illinois, USA
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17
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Lanz M, Cortada M, Lu Y, Levano S, Bodmer D. mTORC2 Regulates Actin Polymerization in Auditory Cells. J Neurochem 2025; 169:e70012. [PMID: 39921391 DOI: 10.1111/jnc.70012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Revised: 01/17/2025] [Accepted: 01/22/2025] [Indexed: 02/10/2025]
Abstract
Mammalian target of rapamycin complex 2 (mTORC2) is essential for hearing by regulating auditory hair cell structure and function. However, mechanistic details of how mTORC2 regulates intracellular processes in sensory hair cells have not yet been clarified. To further elucidate the role of mTORC2 in auditory cells, we generated a Rictor knockout cell line from HEI-OC1 auditory cells. mTORC2-deficient auditory cells exhibited significant alterations in actin cytoskeleton morphology and decreased proliferation rates. Additionally, we observed a reduction in phosphorylation of protein kinase C alpha (PKCα) and disrupted actin polymerization in mTORC2-deficient cells. Using proteomics, we found that mTORC2 disruption altered expression of cytoskeleton-related proteins in auditory cells. These findings provide valuable mechanistic insights into the functional role of mTORC2 in auditory cells, potentially opening new perspectives to address sensorineural hearing loss.
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Affiliation(s)
- Michael Lanz
- Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Maurizio Cortada
- Department of Biomedicine, University of Basel, Basel, Switzerland
- Clinic for Otorhinolaryngology, Head and Neck Surgery, University of Basel Hospital, Basel, Switzerland
| | - Yu Lu
- Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Soledad Levano
- Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Daniel Bodmer
- Department of Biomedicine, University of Basel, Basel, Switzerland
- Clinic for Otorhinolaryngology, Head and Neck Surgery, University of Basel Hospital, Basel, Switzerland
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18
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Zang MX, Zhang G, Zhang Y, Wang SS, Zhai XW, Zhao N, Ge W, Xie JW, Shen W, Cheng SF. mTORC1 regulates the proliferation of SOX9 + porcine skin-derived stem cells (pSDSCs) by promoting S6K phosphorylation. Histochem Cell Biol 2025; 163:25. [PMID: 39833550 DOI: 10.1007/s00418-025-02354-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/06/2025] [Indexed: 01/22/2025]
Abstract
Skin-derived stem cells (SDSCs) are a subtype of adult stem cells (ASCs) that are widely harvested and exempt from ethical restrictions in clinical applications. These cells possess capabilities for self-renewal, proliferation, and multi-lineage differentiation. Compared to model animals like rats and mice, pigs exhibit greater physiological similarity to humans. Porcine skin has very similar histological and physiological characteristics to human skin. Therefore, porcine skin is becoming increasingly significant as an in vitro model for research. In this study, porcine skin-derived stem cells (pSDSCs) were isolated and cultured in vitro for experiments. The expression of stemness-related gene SOX9 was detected. RNA sequencing (RNA-seq) results found that the mammalian target of rapamycin (mTOR) signaling pathway was significantly enriched in SOX9+ pSDSCs. To investigate the role of the mTOR signaling pathway, we added rapamycin (RAPA), an inhibitor of the mTOR complex 1 (mTORC1), and found that the proliferation rate of SOX9+ pSDSCs decreased significantly during culture. In addition, western blotting (WB) results demonstrated that mTORC1 promoted proliferation by phosphorylating S6 kinase (S6K) and then activating cyclin D1(CCND1) in SOX9+ pSDSCs. These findings provide insights into the mechanisms of adult stem cell proliferation.
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Affiliation(s)
- Ming-Xin Zang
- College of Life Sciences, Key Laboratory of Animal Reproduction and Biotechnology in Universities of Shandong, Qingdao Agricultural University, Qingdao, 266109, China
| | - Geng Zhang
- College of Life Sciences, Key Laboratory of Animal Reproduction and Biotechnology in Universities of Shandong, Qingdao Agricultural University, Qingdao, 266109, China
| | - Ying Zhang
- College of Life Sciences, Key Laboratory of Animal Reproduction and Biotechnology in Universities of Shandong, Qingdao Agricultural University, Qingdao, 266109, China
| | - Sha-Sha Wang
- Qingdao Animal Husbandry and Veterinary Institute, Qingdao, 266000, Shandong, China
| | - Xiang-Wei Zhai
- Animal Husbandry General Station of Shandong Province, Jinan, 250010, China
| | - Na Zhao
- College of Life Sciences, Key Laboratory of Animal Reproduction and Biotechnology in Universities of Shandong, Qingdao Agricultural University, Qingdao, 266109, China
| | - Wei Ge
- College of Life Sciences, Key Laboratory of Animal Reproduction and Biotechnology in Universities of Shandong, Qingdao Agricultural University, Qingdao, 266109, China
| | - Jin-Wen Xie
- Shandong Binzhou Animal Science and Veterinary Medicine Academy, Binzhou, 256600, China
| | - Wei Shen
- College of Life Sciences, Key Laboratory of Animal Reproduction and Biotechnology in Universities of Shandong, Qingdao Agricultural University, Qingdao, 266109, China
| | - Shun-Feng Cheng
- College of Life Sciences, Key Laboratory of Animal Reproduction and Biotechnology in Universities of Shandong, Qingdao Agricultural University, Qingdao, 266109, China.
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19
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Jeon S, Jeon Y, Lim JY, Kim Y, Cha B, Kim W. Emerging regulatory mechanisms and functions of biomolecular condensates: implications for therapeutic targets. Signal Transduct Target Ther 2025; 10:4. [PMID: 39757214 DOI: 10.1038/s41392-024-02070-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 10/01/2024] [Accepted: 11/06/2024] [Indexed: 01/07/2025] Open
Abstract
Cells orchestrate their processes through complex interactions, precisely organizing biomolecules in space and time. Recent discoveries have highlighted the crucial role of biomolecular condensates-membrane-less assemblies formed through the condensation of proteins, nucleic acids, and other molecules-in driving efficient and dynamic cellular processes. These condensates are integral to various physiological functions, such as gene expression and intracellular signal transduction, enabling rapid and finely tuned cellular responses. Their ability to regulate cellular signaling pathways is particularly significant, as it requires a careful balance between flexibility and precision. Disruption of this balance can lead to pathological conditions, including neurodegenerative diseases, cancer, and viral infections. Consequently, biomolecular condensates have emerged as promising therapeutic targets, with the potential to offer novel approaches to disease treatment. In this review, we present the recent insights into the regulatory mechanisms by which biomolecular condensates influence intracellular signaling pathways, their roles in health and disease, and potential strategies for modulating condensate dynamics as a therapeutic approach. Understanding these emerging principles may provide valuable directions for developing effective treatments targeting the aberrant behavior of biomolecular condensates in various diseases.
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Affiliation(s)
- Soyoung Jeon
- Department of Life Science, University of Seoul, Seoul, South Korea
| | - Yeram Jeon
- Department of Life Science, University of Seoul, Seoul, South Korea
| | - Ji-Youn Lim
- New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, South Korea
| | - Yujeong Kim
- Department of Life Science, University of Seoul, Seoul, South Korea
| | - Boksik Cha
- New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, South Korea.
| | - Wantae Kim
- Department of Life Science, University of Seoul, Seoul, South Korea.
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20
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Marafie SK, Alshawaf E, Al-Mulla F, Abubaker J, Mohammad A. Targeting mTOR Kinase with Natural Compounds: Potent ATP-Competitive Inhibition Through Enhanced Binding Mechanisms. Pharmaceuticals (Basel) 2024; 17:1677. [PMID: 39770519 PMCID: PMC11677242 DOI: 10.3390/ph17121677] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2024] [Revised: 12/03/2024] [Accepted: 12/09/2024] [Indexed: 01/11/2025] Open
Abstract
Background/Objectives: The mammalian target of the rapamycin (mTOR) signaling pathway is a central regulator of cell growth, proliferation, metabolism, and survival. Dysregulation of mTOR signaling contributes to many human diseases, including cancer, diabetes, and obesity. Therefore, inhibitors against mTOR's catalytic kinase domain (KD) have been developed and have shown significant antitumor activities, making it a promising therapeutic target. The ATP-KD interaction is particularly important for mTOR to exert its cellular functions, and such inhibitors have demonstrated efficient attenuation of overall mTOR activity. Methods: In this study, we screened the Traditional Chinese Medicine (TCM) database, which enlists natural products that capture the relationships between drugs targets and diseases. Our aim was to identify potential ATP-competitive agonists that target the mTOR-KD and compete with ATP to bind the mTOR-KD serving as potential potent mTOR inhibitors. Results: We identified two compounds that demonstrated interatomic interactions similar to those of ATP-mTOR. The conformational stability and dynamic features of the mTOR-KD bound to the selected compounds were tested by subjecting each complex to 200 ns molecular dynamic (MD) simulations and molecular mechanics/generalized Born surface area (MM/GBSA) to extract free binding energies. We show the effectiveness of both compounds in forming stable complexes with the mTOR-KD, which is more effective than the mTOR-KD-ATP complex with more robust binding affinities. Conclusions: This study implies that both compounds could serve as potential therapeutic inhibitors of mTOR, regulating its function and, therefore, mitigating human disease progression.
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Affiliation(s)
- Sulaiman K. Marafie
- Biochemistry and Molecular Biology Department, Dasman Diabetes Institute, Dasman 15462, Kuwait; (S.K.M.); (E.A.)
| | - Eman Alshawaf
- Biochemistry and Molecular Biology Department, Dasman Diabetes Institute, Dasman 15462, Kuwait; (S.K.M.); (E.A.)
| | - Fahd Al-Mulla
- Translational Research Department, Dasman Diabetes Institute, Dasman 15462, Kuwait;
| | - Jehad Abubaker
- Biochemistry and Molecular Biology Department, Dasman Diabetes Institute, Dasman 15462, Kuwait; (S.K.M.); (E.A.)
| | - Anwar Mohammad
- Biochemistry and Molecular Biology Department, Dasman Diabetes Institute, Dasman 15462, Kuwait; (S.K.M.); (E.A.)
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21
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Hochmuth L, Hirrlinger J. Physiological and Pathological Role of mTOR Signaling in Astrocytes. Neurochem Res 2024; 50:53. [PMID: 39652154 PMCID: PMC11628441 DOI: 10.1007/s11064-024-04306-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Revised: 11/20/2024] [Accepted: 12/02/2024] [Indexed: 12/12/2024]
Abstract
The mammalian target of rapamycin (mTOR) signaling pathway is one of the key regulators of cellular energy metabolism. It senses diverse alterations in the extracellular environment such as availability of nutrients and growth factors, and mediates the corresponding intracellular response. In the brain, astrocytes crucially contribute to energy and neurotransmitter metabolism, and numerous other functions. However, the relevance of physiological, astrocytic mTOR signaling in maintaining brain homeostasis and function is not well understood. Pathophysiological mTOR signaling is involved in manifold diseases in the central nervous system and most of the knowledge about astrocytic mTOR signaling has been derived from observations on these disorders. Dysregulation of the mTOR signaling pathway impairs important functions of astrocytes including neurotransmitter uptake and -signaling as well as energy metabolism. Some of these alterations could trigger neuropathological conditions such as epilepsy. This review focuses on how mTOR signaling regulates properties of astrocytes, and how these signaling events might contribute to the physiological function of the brain.
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Affiliation(s)
- Luise Hochmuth
- Carl-Ludwig-Institute for Physiology, Faculty of Medicine, University of Leipzig, D- 04103, Leipzig, Germany.
| | - Johannes Hirrlinger
- Carl-Ludwig-Institute for Physiology, Faculty of Medicine, University of Leipzig, D- 04103, Leipzig, Germany.
- Department of Neurogenetics, Max-Planck-Institute for Multidisciplinary Sciences, D- 37075, Göttingen, Germany.
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22
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Sluzala ZB, Shan Y, Elghazi L, Cárdenas EL, Hamati A, Garner AL, Fort PE. Novel mTORC2/HSPB4 Interaction: Role and Regulation of HSPB4 T148 Phosphorylation. Cells 2024; 13:2000. [PMID: 39682748 PMCID: PMC11640050 DOI: 10.3390/cells13232000] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Revised: 11/23/2024] [Accepted: 11/27/2024] [Indexed: 12/18/2024] Open
Abstract
HSPB4 and HSPB5 (α-crystallins) have shown increasing promise as neuroprotective agents, demonstrating several anti-apoptotic and protective roles in disorders such as multiple sclerosis and diabetic retinopathy. HSPs are highly regulated by post-translational modification, including deamidation, glycosylation, and phosphorylation. Among them, T148 phosphorylation has been shown to regulate the structural and functional characteristics of HSPB4 and underlie, in part, its neuroprotective capacity. We recently demonstrated that this phosphorylation is reduced in retinal tissues from patients with diabetic retinopathy, raising the question of its regulation during diseases. The kinase(s) responsible for regulating this phosphorylation, however, have yet to be identified. To this end, we employed a multi-tier strategy utilizing in vitro kinome profiling, bioinformatics, and chemoproteomics to predict and discover the kinases capable of phosphorylating T148. Several kinases were identified as being capable of specifically phosphorylating T148 in vitro, and further analysis highlighted mTORC2 as a particularly strong candidate. Altogether, our data demonstrate that the HSPB4-mTORC2 interaction is multi-faceted. Our data support the role of mTORC2 as a specific kinase phosphorylating HSPB4 at T148, but also provide evidence that the HSPB4 chaperone function further strengthens the interaction. This study addresses a critical gap in our understanding of the regulatory underpinnings of T148 phosphorylation-mediated neuroprotection.
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Affiliation(s)
- Zachary B. Sluzala
- Department of Ophthalmology & Visual Sciences, The University of Michigan, Ann Arbor, MI 48109, USA; (Z.B.S.); (Y.S.); (L.E.); (A.H.)
| | - Yang Shan
- Department of Ophthalmology & Visual Sciences, The University of Michigan, Ann Arbor, MI 48109, USA; (Z.B.S.); (Y.S.); (L.E.); (A.H.)
| | - Lynda Elghazi
- Department of Ophthalmology & Visual Sciences, The University of Michigan, Ann Arbor, MI 48109, USA; (Z.B.S.); (Y.S.); (L.E.); (A.H.)
| | - Emilio L. Cárdenas
- Interdepartmental Program in Medicinal Chemistry, The University of Michigan, Ann Arbor, MI 48109, USA; (E.L.C.); (A.L.G.)
| | - Angelina Hamati
- Department of Ophthalmology & Visual Sciences, The University of Michigan, Ann Arbor, MI 48109, USA; (Z.B.S.); (Y.S.); (L.E.); (A.H.)
| | - Amanda L. Garner
- Interdepartmental Program in Medicinal Chemistry, The University of Michigan, Ann Arbor, MI 48109, USA; (E.L.C.); (A.L.G.)
| | - Patrice E. Fort
- Department of Ophthalmology & Visual Sciences, The University of Michigan, Ann Arbor, MI 48109, USA; (Z.B.S.); (Y.S.); (L.E.); (A.H.)
- Department of Molecular & Integrative Physiology, The University of Michigan, Ann Arbor, MI 48109, USA
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23
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Cao Z, Tian K, Ran Y, Zhou H, Zhou L, Ding Y, Tang X. Beclin-1: a therapeutic target at the intersection of autophagy, immunotherapy, and cancer treatment. Front Immunol 2024; 15:1506426. [PMID: 39650649 PMCID: PMC11621085 DOI: 10.3389/fimmu.2024.1506426] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2024] [Accepted: 11/01/2024] [Indexed: 12/11/2024] Open
Abstract
The significant identification of Beclin-1's function in regulating autophagy flow signified a significant progression in our understanding of cellular operations. Beclin-1 acts as a scaffold for forming the PI3KC3 complex, controlling autophagy and cellular trafficking processes in a complicated way. This intricate protein has garnered considerable attention due to its substantial impact on the development of tumors. Strong evidence indicates Beclin-1 plays a critical role in controlling autophagy in various human cancer types and its intricate connection with apoptosis and ferroptosis. The potential of Beclin-1 as a viable target for cancer therapy is highlighted by its associations with key autophagy regulators such as AMPK, mTOR, and ATGs. Beclin-1 controls the growth and dissemination of tumors by autophagy. It also affects how tumors react to therapies such as chemotherapy and radiation therapy. The role of Beclin-1 in autophagy can influence apoptosis, depending on whether it supports cell survival or leads to cell death. Beclin-1 plays a crucial role in ferroptosis by increasing ATG5 levels, which in turn promotes autophagy-triggered ferroptosis. Finally, we analyzed the possible function of Beclin-1 in tumor immunology and drug sensitivity in cancers. In general, Beclin-1 has a significant impact on regulating autophagy, offering various potentials for medical intervention and altering our understanding of cancer biology.
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Affiliation(s)
- Zhumin Cao
- Department of Hepatobiliary Surgery, The Seventh People’s Hospital of Chongqing, Chongqing, China
| | - Ke Tian
- Department of Hepatobiliary Surgery, The Seventh People’s Hospital of Chongqing, Chongqing, China
| | - Yincheng Ran
- Department of Hepatobiliary Surgery, The Seventh People’s Hospital of Chongqing, Chongqing, China
| | - Haonan Zhou
- Department of Hepatobiliary Surgery, The Seventh People’s Hospital of Chongqing, Chongqing, China
| | - Lei Zhou
- Department of Hepatobiliary Surgery, The Seventh People’s Hospital of Chongqing, Chongqing, China
| | - Yana Ding
- Department of Hepatobiliary Surgery, District Traditional Chinese Medicine Hospital, Chongqing, China
| | - Xiaowei Tang
- Department of Hepatobiliary Surgery, District Traditional Chinese Medicine Hospital, Chongqing, China
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24
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Seo D, Yalcin G, Jang H, Lee HJ, Kim DH, Lee CK. TOR2 plays the central role in rapamycin-induced lifespan extension in budding yeast. Biochem Biophys Res Commun 2024; 734:150639. [PMID: 39241621 DOI: 10.1016/j.bbrc.2024.150639] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Accepted: 08/31/2024] [Indexed: 09/09/2024]
Abstract
The target of rapamycin (TOR) protein, renowned for its highly conserved nature across species, plays a pivotal role in modulating signaling pathways via its multiprotein complexes, TORC1 and TORC2. The relationship between TOR and its inhibitor, rapamycin, especially in the context of lifespan extension, has earned significant attention. Unlike mammals, which have a single TOR gene, the budding yeast Saccharomyces cerevisiae features two TOR paralogs: TOR1 and TOR2. Non-essential TOR1 gene has been the focus of extensive research, whereas the essential TOR2 gene has received relatively little attention in lifespan studies. In our research, we engineered a point mutation (Ser-1975-Ile) within the FKBP12-rapamycin-binding (FRB) domain of Tor2p to block rapamycin binding. Remarkably, this mutation negated the lifespan-extending benefits of rapamycin, irrespective of the TOR1 gene status. Our findings indicate that the TOR2 gene likely serves as the primary mammalian ortholog, playing a crucial role in mediating the effects of rapamycin on lifespan extension. This discovery opens a new avenue for the development of innovative anti-aging agents targeting the TOR. complex.
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Affiliation(s)
- Dongseong Seo
- Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, 02481, Republic of Korea
| | - Gulperi Yalcin
- Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, 02481, Republic of Korea
| | - Hyeonjun Jang
- Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, 02481, Republic of Korea
| | - Han-Jun Lee
- Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, 02481, Republic of Korea
| | - Deok Ho Kim
- Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, 02481, Republic of Korea
| | - Cheol-Koo Lee
- Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, 02481, Republic of Korea.
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25
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Alesi N, Asrani K, Lotan TL, Henske EP. The Spectrum of Renal "TFEopathies": Flipping the mTOR Switch in Renal Tumorigenesis. Physiology (Bethesda) 2024; 39:0. [PMID: 39012319 DOI: 10.1152/physiol.00026.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Revised: 07/11/2024] [Accepted: 07/11/2024] [Indexed: 07/17/2024] Open
Abstract
The mammalian target of Rapamycin complex 1 (mTORC1) is a serine/threonine kinase that couples nutrient and growth factor signaling to the cellular control of metabolism and plays a fundamental role in aberrant proliferation in cancer. mTORC1 has previously been considered an "on/off" switch, capable of phosphorylating the entire pool of its substrates when activated. However, recent studies have indicated that mTORC1 may be active toward its canonical substrates, eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1) and S6 kinase (S6K), involved in mRNA translation and protein synthesis, and inactive toward TFEB and TFE3, transcription factors involved in the regulation of lysosome biogenesis, in several pathological contexts. Among these conditions are Birt-Hogg-Dubé syndrome (BHD) and, recently, tuberous sclerosis complex (TSC). Furthermore, increased TFEB and TFE3 nuclear localization in these syndromes, and in translocation renal cell carcinomas (tRCC), drives mTORC1 activity toward the canonical substrates, through the transcriptional activation of the Rag GTPases, thereby positioning TFEB and TFE3 upstream of mTORC1 activity toward 4EBP1 and S6K. The expanding importance of TFEB and TFE3 in the pathogenesis of these renal diseases warrants a novel clinical grouping that we term "TFEopathies." Currently, there are no therapeutic options directly targeting TFEB and TFE3, which represents a challenging and critically required avenue for cancer research.
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Affiliation(s)
- Nicola Alesi
- Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
| | - Kaushal Asrani
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
| | - Tamara L Lotan
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
| | - Elizabeth P Henske
- Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States
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26
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Xu W, Chen H, Xiao H. mTORC2: A neglected player in aging regulation. J Cell Physiol 2024; 239:e31363. [PMID: 38982866 DOI: 10.1002/jcp.31363] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Revised: 05/21/2024] [Accepted: 06/19/2024] [Indexed: 07/11/2024]
Abstract
Mammalian target of rapamycin (mTOR) is a serine/threonine kinase that plays a pivotal role in various biological processes, through integrating external and internal signals, facilitating gene transcription and protein translation, as well as by regulating mitochondria and autophagy functions. mTOR kinase operates within two distinct protein complexes known as mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), which engage separate downstream signaling pathways impacting diverse cellular processes. Although mTORC1 has been extensively studied as a pro-proliferative factor and a pro-aging hub if activated aberrantly, mTORC2 received less attention, particularly regarding its implication in aging regulation. However, recent studies brought increasing evidence or clues for us, which implies the associations of mTORC2 with aging, as the genetic elimination of unique subunits of mTORC2, such as RICTOR, has been shown to alleviate aging progression in comparison to mTORC1 inhibition. In this review, we first summarized the basic characteristics of mTORC2, including its protein architecture and signaling network. We then focused on reviewing the molecular signaling regulation of mTORC2 in cellular senescence and organismal aging, and proposed the multifaceted regulatory characteristics under senescent and nonsenescent contexts. Next, we outlined the research progress of mTOR inhibitors in the field of antiaging and discussed future prospects and challenges. It is our pleasure if this review article could provide meaningful information for our readers and call forth more investigations working on this topic.
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Affiliation(s)
- Weitong Xu
- The Lab of Aging Research, National Clinical Research Center for Geriatrics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Honghan Chen
- The Lab of Aging Research, National Clinical Research Center for Geriatrics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Hengyi Xiao
- The Lab of Aging Research, National Clinical Research Center for Geriatrics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
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27
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Yildirim E, Onel T, Agus S, Gunalan E, Yilmaz B, Aydin MS, Yaba A. The effect of rapamycin treatment on mouse ovarian follicle development in dehydroepiandrosterone-induced polycystic ovary syndrome mouse model. ZYGOTE 2024; 32:386-395. [PMID: 39498504 DOI: 10.1017/s0967199424000388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2024]
Abstract
Polycystic ovary syndrome (PCOS) is a complex reproductive and endocrine disorder affecting 5-10% of women of reproductive age, but the pathophysiology of PCOS still remains unknown. Here, the aim of our study was to analyze the effects of rapamycin treatment that may regulate impaired hormonal levels and folliculogenesis in dehydroepiandrosterone (DHEA)-treated PCOS mouse. We hypothesized that rapamycin may ameliorate the negative effects of PCOS in DHEA-induced PCOS mouse model. The target of rapamycin (TOR) gene product is a serine/threonine kinase that has been implicated in the control of cell growth, proliferation and autophagy, and rapamycin is a potent inhibitor of mTORC1 pathway. In this study, for the first time, mTORC1 and activation products are presented at protein and mRNA levels after rapamycin treatment in DHEA-induced PCOS mouse ovary. We showed that rapamycin treatment may regulate follicular development, hormonal levels and provide ovulation in DHEA-induced PCOS mouse. Additionally, we assessed decreased primordial follicle reserve, increased number of primary and secondary follicles, corpus luteum structure forms again after 10 days of rapamycin treatment. This study presented here suggests rapamycin treatment regulates hormonal phenotype and folliculogenesis in the ovary and also mTOR signalling pathway in granulosa cells of DHEA-induced PCOS mouse ovary which may have potential to attenuate understanding the mechanism of dominant follicle selection and anovulatory infertility.
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Affiliation(s)
- Ecem Yildirim
- Yeditepe University Faculty of Medicine, Department of Histology and Embryology, İstanbul, Turkey
| | - Tugce Onel
- Yeditepe University Faculty of Medicine, Department of Histology and Embryology, İstanbul, Turkey
| | - Sami Agus
- Yeditepe University Faculty of Medicine, Department of Physiology, İstanbul, Turkey
| | - Elif Gunalan
- Istanbul Health and Technology University, Faculty of Health Science, Department of Nutrition and Dietetics, Istanbul, Turkey
| | - Bayram Yilmaz
- Yeditepe University Faculty of Medicine, Department of Physiology, İstanbul, Turkey
| | - Mehmet Serif Aydin
- Regenerative and Restorative Medicine Research Center, Istanbul Medipol University, Istanbul, Turkey
| | - Aylin Yaba
- Yeditepe University Faculty of Medicine, Department of Histology and Embryology, İstanbul, Turkey
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28
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Yue L, Li J, Yao M, Song S, Zhang X, Wang Y. Cutting edge of immune response and immunosuppressants in allogeneic and xenogeneic islet transplantation. Front Immunol 2024; 15:1455691. [PMID: 39346923 PMCID: PMC11427288 DOI: 10.3389/fimmu.2024.1455691] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Accepted: 08/27/2024] [Indexed: 10/01/2024] Open
Abstract
As an effective treatment for diabetes, islet transplantation has garnered significant attention and research in recent years. However, immune rejection and the toxicity of immunosuppressive drugs remain critical factors influencing the success of islet transplantation. While immunosuppressants are essential in reducing immune rejection reactions and can significantly improve the survival rate of islet transplants, improper use of these drugs can markedly increase mortality rates following transplantation. Additionally, the current availability of islet organ donations fails to meet the demand for organ transplants, making xenotransplantation a crucial method for addressing organ shortages. This review will cover the following three aspects: 1) the immune responses occurring during allogeneic islet transplantation, including three stages: inflammation and IBMIR, allogeneic immune response, and autoimmune recurrence; 2) commonly used immunosuppressants in allogeneic islet transplantation, including calcineurin inhibitors (Cyclosporine A, Tacrolimus), mycophenolate mofetil, glucocorticoids, and Bortezomib; and 3) early and late immune responses in xenogeneic islet transplantation and the immune effects of triple therapy (ECDI-fixed donor spleen cells (ECDI-SP) + anti-CD20 + Sirolimus) on xenotransplantation.
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Affiliation(s)
- Liting Yue
- Center of Critical Care Medicine, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Jisong Li
- Department of Gastrointestinal Surgery, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Mingjun Yao
- Center of Critical Care Medicine, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Siyuan Song
- Department of Neuroscience, Baylor College of Medicine, Houston, TX, United States
| | - Xiaoqin Zhang
- Center of Critical Care Medicine, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Yi Wang
- Center of Critical Care Medicine, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Sichuan Provincial People’s Hospital, Chengdu, China
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Emamnejad R, Pagnin M, Petratos S. The iron maiden: Oligodendroglial metabolic dysfunction in multiple sclerosis and mitochondrial signaling. Neurosci Biobehav Rev 2024; 164:105788. [PMID: 38950685 DOI: 10.1016/j.neubiorev.2024.105788] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Revised: 06/06/2024] [Accepted: 06/24/2024] [Indexed: 07/03/2024]
Abstract
Multiple sclerosis (MS) is an autoimmune disease, governed by oligodendrocyte (OL) dystrophy and central nervous system (CNS) demyelination manifesting variable neurological impairments. Mitochondrial mechanisms may drive myelin biogenesis maintaining the axo-glial unit according to dynamic requisite demands imposed by the axons they ensheath. The promotion of OL maturation and myelination by actively transporting thyroid hormone (TH) into the CNS and thereby facilitating key transcriptional and metabolic pathways that regulate myelin biogenesis is fundamental to sustain the profound energy demands at each axo-glial interface. Deficits in regulatory functions exerted through TH for these physiological roles to be orchestrated by mature OLs, can occur in genetic and acquired myelin disorders, whereby mitochondrial efficiency and eventual dysfunction can lead to profound oligodendrocytopathy, demyelination and neurodegenerative sequelae. TH-dependent transcriptional and metabolic pathways can be dysregulated during acute and chronic MS lesion activity depriving OLs from critical acetyl-CoA biochemical mechanisms governing myelin lipid biosynthesis and at the same time altering the generation of iron metabolism that may drive ferroptotic mechanisms, leading to advancing neurodegeneration.
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Affiliation(s)
- Rahimeh Emamnejad
- Department of Neuroscience, Central Clinical School, Monash University, Prahran, Victoria 3004, Australia.
| | - Maurice Pagnin
- Department of Neuroscience, Central Clinical School, Monash University, Prahran, Victoria 3004, Australia.
| | - Steven Petratos
- Department of Neuroscience, Central Clinical School, Monash University, Prahran, Victoria 3004, Australia.
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El Hajji S, Shiga Y, Belforte N, Solorio YC, Tastet O, D’Onofrio P, Dotigny F, Prat A, Arbour N, Fortune B, Di Polo A. Insulin restores retinal ganglion cell functional connectivity and promotes visual recovery in glaucoma. SCIENCE ADVANCES 2024; 10:eadl5722. [PMID: 39110798 PMCID: PMC11305393 DOI: 10.1126/sciadv.adl5722] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/02/2023] [Accepted: 06/28/2024] [Indexed: 08/10/2024]
Abstract
Dendrite pathology and synaptic loss result in neural circuit dysfunction, a common feature of neurodegenerative diseases. There is a lack of strategies that target dendritic and synaptic regeneration to promote neurorecovery. We show that daily human recombinant insulin eye drops stimulate retinal ganglion cell (RGC) dendrite and synapse regeneration during ocular hypertension, a risk factor to develop glaucoma. We demonstrate that the ribosomal protein p70S6 kinase (S6K) is essential for insulin-dependent dendritic regrowth. Furthermore, S6K phosphorylation of the stress-activated protein kinase-interacting protein 1 (SIN1), a link between the mammalian target of rapamycin complexes 1 and 2 (mTORC1/2), is required for insulin-induced dendritic regeneration. Using two-photon microscopy live retinal imaging, we show that insulin rescues single-RGC light-evoked calcium (Ca2+) dynamics. We further demonstrate that insulin enhances neuronal survival and retina-brain connectivity leading to improved optomotor reflex-elicited behaviors. Our data support that insulin is a compelling pro-regenerative strategy with potential clinical implications for the treatment and management of glaucoma.
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Affiliation(s)
- Sana El Hajji
- Department of Neuroscience, Université de Montréal, PO box 6128, Station centre-ville, Montreal, Quebec, Canada
- Neuroscience Division, Centre de recherche du Centre Hospitalier de l’Université de Montréal (CR-CHUM), 900 Saint Denis Street, Montreal, Quebec, Canada
| | - Yukihiro Shiga
- Department of Neuroscience, Université de Montréal, PO box 6128, Station centre-ville, Montreal, Quebec, Canada
- Neuroscience Division, Centre de recherche du Centre Hospitalier de l’Université de Montréal (CR-CHUM), 900 Saint Denis Street, Montreal, Quebec, Canada
| | - Nicolas Belforte
- Department of Neuroscience, Université de Montréal, PO box 6128, Station centre-ville, Montreal, Quebec, Canada
- Neuroscience Division, Centre de recherche du Centre Hospitalier de l’Université de Montréal (CR-CHUM), 900 Saint Denis Street, Montreal, Quebec, Canada
| | - Yves Carpentier Solorio
- Department of Neuroscience, Université de Montréal, PO box 6128, Station centre-ville, Montreal, Quebec, Canada
- Neuroscience Division, Centre de recherche du Centre Hospitalier de l’Université de Montréal (CR-CHUM), 900 Saint Denis Street, Montreal, Quebec, Canada
| | - Olivier Tastet
- Department of Neuroscience, Université de Montréal, PO box 6128, Station centre-ville, Montreal, Quebec, Canada
- Neuroscience Division, Centre de recherche du Centre Hospitalier de l’Université de Montréal (CR-CHUM), 900 Saint Denis Street, Montreal, Quebec, Canada
| | - Philippe D’Onofrio
- Department of Neuroscience, Université de Montréal, PO box 6128, Station centre-ville, Montreal, Quebec, Canada
- Neuroscience Division, Centre de recherche du Centre Hospitalier de l’Université de Montréal (CR-CHUM), 900 Saint Denis Street, Montreal, Quebec, Canada
| | - Florence Dotigny
- Department of Neuroscience, Université de Montréal, PO box 6128, Station centre-ville, Montreal, Quebec, Canada
- Neuroscience Division, Centre de recherche du Centre Hospitalier de l’Université de Montréal (CR-CHUM), 900 Saint Denis Street, Montreal, Quebec, Canada
| | - Alexandre Prat
- Department of Neuroscience, Université de Montréal, PO box 6128, Station centre-ville, Montreal, Quebec, Canada
- Neuroscience Division, Centre de recherche du Centre Hospitalier de l’Université de Montréal (CR-CHUM), 900 Saint Denis Street, Montreal, Quebec, Canada
| | - Nathalie Arbour
- Department of Neuroscience, Université de Montréal, PO box 6128, Station centre-ville, Montreal, Quebec, Canada
- Neuroscience Division, Centre de recherche du Centre Hospitalier de l’Université de Montréal (CR-CHUM), 900 Saint Denis Street, Montreal, Quebec, Canada
| | - Brad Fortune
- Discoveries in Sight Research Laboratories, Devers Eye Institute and Legacy Research Institute, Legacy Health, Portland, OR, USA
| | - Adriana Di Polo
- Department of Neuroscience, Université de Montréal, PO box 6128, Station centre-ville, Montreal, Quebec, Canada
- Neuroscience Division, Centre de recherche du Centre Hospitalier de l’Université de Montréal (CR-CHUM), 900 Saint Denis Street, Montreal, Quebec, Canada
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31
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Chen Y, Zhang Y, Duo S, Liu W, Luo B. Study on the regulatory mechanism of latent membrane protein 2A on GCNT3 expression in nasopharyngeal carcinoma. Virus Genes 2024; 60:347-356. [PMID: 38739247 DOI: 10.1007/s11262-024-02071-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Accepted: 04/06/2024] [Indexed: 05/14/2024]
Abstract
O-Glycan synthesis enzyme glucosaminyl (N-acetyl) transferase 3 (GCNT3) is closely related to the occurrence and development of various cancers. However, the regulatory mechanism and function of GCNT3 in nasopharyngeal carcinoma (NPC) are still poorly understood. This study aims to explore the regulatory mechanism of EBV-encoded latent membrane protein 2A (LMP2A) on GCNT3 and the biological role of GCNT3 in NPC. The results show that LMP2A can activate GCNT3 through the mTORC1 pathway, and there is a positive feedback between the mTORC1 and GCNT3. GCNT3 regulates EMT progression by forming a complex with ZEB1 to promote cell migration. GCNT3 can also promote cell proliferation. These findings indicate that targeting the LMP2A-mTORC1-GCNT3 axis may represent a novel therapeutic target in NPC.
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Affiliation(s)
- Yijing Chen
- Department of Pathogenic Biology, School of Basic Medicine, Qingdao University, Qingdao, China
- Department of Clinical Laboratory, The Sixth Hospital of Wuhan, Affiliated Hospital of Jianghan University, Wuhan, China
| | - Yan Zhang
- Department of Pathogenic Biology, School of Basic Medicine, Qingdao University, Qingdao, China
- Department of Clinical Laboratory, Central Hospital of Zibo, Zibo, China
| | - Shi Duo
- Department of Pathogenic Biology, School of Basic Medicine, Qingdao University, Qingdao, China
| | - Wen Liu
- Department of Pathogenic Biology, School of Basic Medicine, Qingdao University, Qingdao, China.
| | - Bing Luo
- Department of Pathogenic Biology, School of Basic Medicine, Qingdao University, Qingdao, China.
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32
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Darawshi O, Yassin O, Shmuel M, Wek RC, Mahdizadeh SJ, Eriksson LA, Hatzoglou M, Tirosh B. Phosphorylation of GCN2 by mTOR confers adaptation to conditions of hyper-mTOR activation under stress. J Biol Chem 2024; 300:107575. [PMID: 39013537 PMCID: PMC11362803 DOI: 10.1016/j.jbc.2024.107575] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2024] [Revised: 07/02/2024] [Accepted: 07/05/2024] [Indexed: 07/18/2024] Open
Abstract
Adaptation to the shortage in free amino acids (AA) is mediated by 2 pathways, the integrated stress response (ISR) and the mechanistic target of rapamycin (mTOR). In response to reduced levels, primarily of leucine or arginine, mTOR in its complex 1 configuration (mTORC1) is suppressed leading to a decrease in translation initiation and elongation. The eIF2α kinase general control nonderepressible 2 (GCN2) is activated by uncharged tRNAs, leading to induction of the ISR in response to a broader range of AA shortage. ISR confers a reduced translation initiation, while promoting the selective synthesis of stress proteins, such as ATF4. To efficiently adapt to AA starvation, the 2 pathways are cross-regulated at multiple levels. Here we identified a new mechanism of ISR/mTORC1 crosstalk that optimizes survival under AA starvation, when mTORC1 is forced to remain active. mTORC1 activation during acute AA shortage, augmented ATF4 expression in a GCN2-dependent manner. Under these conditions, enhanced GCN2 activity was not dependent on tRNA sensing, inferring a different activation mechanism. We identified a labile physical interaction between GCN2 and mTOR that results in a phosphorylation of GCN2 on serine 230 by mTOR, which promotes GCN2 activity. When examined under prolonged AA starvation, GCN2 phosphorylation by mTOR promoted survival. Our data unveils an adaptive mechanism to AA starvation, when mTORC1 evades inhibition.
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Affiliation(s)
- Odai Darawshi
- The School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Olaya Yassin
- The School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Miri Shmuel
- The School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Ronald C Wek
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - S Jalil Mahdizadeh
- Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden
| | - Leif A Eriksson
- Department of Chemistry and Molecular Biology, University of Gothenburg, Gothenburg, Sweden
| | - Maria Hatzoglou
- Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, Ohio, USA
| | - Boaz Tirosh
- Department of Biochemistry, Case Western Reserve University, Cleveland, Ohio, USA.
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Khaliq SA, Kim J, Kim IC, Kim JH, Yoon MS. The Extracts from Two Antarctic Fish Species, Trematomus newnesi and Trematomus bernacchii, Enhance JEG-3 Cell Migration and Invasion via MMP9 Activation Through Akt/Protein Phosphatase1/β-Catenin Pathway. Mol Nutr Food Res 2024; 68:e2400028. [PMID: 38925577 DOI: 10.1002/mnfr.202400028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Revised: 06/02/2024] [Indexed: 06/28/2024]
Abstract
SCOPE This study investigates the impact of extracts derived from Antarctic fish species, Trematomus newnesi and Trematomus bernacchii, on the migration of human placental trophoblast JEG-3 cells, which is a crucial aspect of successful pregnancy. METHODS AND RESULTS The extracts, obtained from the muscles of these fish, significantly enhance the migration and invasion of JEG-3 cells in in vitro wound healing, Transwell, and collagen invasion assays. These effects are accompanied by an increase in matrix metalloproteinase (MMP) 9 activity, as demonstrated by zymography. Furthermore, the extracts activated Akt and protein phosphatase 1, resulting in the dephosphorylation of β-catenin at Ser33/37/Thr41, as confirmed by western blot analysis. Consequently, MMP9 is upregulated, while metallopeptidase inhibitor 1/3 is downregulated, as verified by western blot and qRT-PCR analyses. Finally, utilizing ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) analysis, followed by matching with the Global Natural Product Social Molecular Networking library, the study annotates the compound responsible for the observed migratory activity as taurocholic acid. Importantly, the study confirms that taurocholic acid enhances cell migration in JEG-3 cells. CONCLUSION The results of this study emphasize the potential of Antarctic fish extracts in promoting extravillous trophoblast migration and invasion, which are critical for successful pregnancy.
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Affiliation(s)
- Sana Abdul Khaliq
- Department of Health Sciences and Technology, Gachon Advanced Institute for Health Science & Technology, Gachon University, Incheon, 21999, Republic of Korea
| | - Jaewon Kim
- Division of Life Sciences, Korea Polar Research Institute, Incheon, 21990, Republic of Korea
- Department of Plant Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, 02841, Republic of Korea
| | - Il-Chan Kim
- Division of Life Sciences, Korea Polar Research Institute, Incheon, 21990, Republic of Korea
| | - Jin-Hyoung Kim
- Division of Life Sciences, Korea Polar Research Institute, Incheon, 21990, Republic of Korea
- Polar Science, University of Science and Technology, Incheon, 21990, Republic of Korea
| | - Mee-Sup Yoon
- Department of Health Sciences and Technology, Gachon Advanced Institute for Health Science & Technology, Gachon University, Incheon, 21999, Republic of Korea
- Department of Molecular Medicine, College of Medicine, Gachon University, Incheon, 21999, Republic of Korea
- Lee Gil Ya Cancer and Diabetes Institute, Incheon, 21999, Republic of Korea
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Li X, Cheng K, Shang MD, Yang Y, Hu B, Wang X, Wei XD, Han YC, Zhang XG, Dong MH, Yang ZL, Wang JQ. MARCH1 negatively regulates TBK1-mTOR signaling pathway by ubiquitinating TBK1. BMC Cancer 2024; 24:902. [PMID: 39061024 PMCID: PMC11282859 DOI: 10.1186/s12885-024-12667-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Accepted: 07/22/2024] [Indexed: 07/28/2024] Open
Abstract
BACKGROUND TBK1 positively regulates the growth factor-mediated mTOR signaling pathway by phosphorylating mTOR. However, it remains unclear how the TBK1-mTOR signaling pathway is regulated. Considering that STING not only interacts with TBK1 but also with MARCH1, we speculated that MARCH1 might regulate the mTOR signaling pathway by targeting TBK1. The aim of this study was to determine whether MARCH1 regulates the mTOR signaling pathway by targeting TBK1. METHODS The co-immunoprecipitation (Co-IP) assay was used to verify the interaction between MARCH1 with STING or TBK1. The ubiquitination of STING or TBK1 was analyzed using denatured co-immunoprecipitation. The level of proteins detected in the co-immunoprecipitation or denatured co-immunoprecipitation samples were determined by Western blotting. Stable knocked-down cells were constructed by infecting lentivirus bearing the related shRNA sequences. Scratch wound healing and clonogenic cell survival assays were used to detect the migration and proliferation of breast cancer cells. RESULTS We showed that MARCH1 played an important role in growth factor-induced the TBK1- mTOR signaling pathway. MARCH1 overexpression attenuated the growth factor-induced activation of mTOR signaling pathway, whereas its deficiency resulted in the opposite effect. Mechanistically, MARCH1 interacted with and promoted the K63-linked ubiquitination of TBK1. This ubiquitination of TBK1 then attenuated its interaction with mTOR, thereby inhibiting the growth factor-induced mTOR signaling pathway. Importantly, faster proliferation induced by MARCH1 deficiency was weakened by mTOR, STING, or TBK1 inhibition. CONCLUSION MARCH1 suppressed growth factors mediated the mTOR signaling pathway by targeting the STING-TBK1-mTOR axis.
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Affiliation(s)
- Xiao Li
- The Second Clinical Medical College , Binzhou Medical University, Yantai, Shandong, 264003, P.R. China
| | - Kai Cheng
- The Second Clinical Medical College , Binzhou Medical University, Yantai, Shandong, 264003, P.R. China
| | - Meng-Di Shang
- Peninsular Cancer Research Center, Binzhou Medical University, Yantai, Shandong, 264003, P.R. China
| | - Yong Yang
- The First School of Clinical Medicine, Binzhou Medical University, Binzhou, Shandong, 256603, P.R. China
| | - Bin Hu
- The First School of Clinical Medicine, Binzhou Medical University, Binzhou, Shandong, 256603, P.R. China
| | - Xi Wang
- School of Basic Medical, Binzhou Medical University, Yantai, Shandong, 264003, P.R. China
| | - Xiao-Dan Wei
- School of Basic Medical, Binzhou Medical University, Yantai, Shandong, 264003, P.R. China
| | - Yan-Chun Han
- School of Basic Medical, Binzhou Medical University, Yantai, Shandong, 264003, P.R. China
| | - Xiao-Gang Zhang
- School of Rehabilitation Medicine, Binzhou Medical University, Yantai, 264003, China
| | - Meng-Hua Dong
- School of Basic Medical, Binzhou Medical University, Yantai, Shandong, 264003, P.R. China.
| | - Zhen-Lin Yang
- The First School of Clinical Medicine, Binzhou Medical University, Binzhou, Shandong, 256603, P.R. China.
| | - Jiu-Qiang Wang
- Peninsular Cancer Research Center, Binzhou Medical University, Yantai, Shandong, 264003, P.R. China.
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Emery B, Wood TL. Regulators of Oligodendrocyte Differentiation. Cold Spring Harb Perspect Biol 2024; 16:a041358. [PMID: 38503504 PMCID: PMC11146316 DOI: 10.1101/cshperspect.a041358] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/21/2024]
Abstract
Myelination has evolved as a mechanism to ensure fast and efficient propagation of nerve impulses along axons. Within the central nervous system (CNS), myelination is carried out by highly specialized glial cells, oligodendrocytes. The formation of myelin is a prolonged aspect of CNS development that occurs well into adulthood in humans, continuing throughout life in response to injury or as a component of neuroplasticity. The timing of myelination is tightly tied to the generation of oligodendrocytes through the differentiation of their committed progenitors, oligodendrocyte precursor cells (OPCs), which reside throughout the developing and adult CNS. In this article, we summarize our current understanding of some of the signals and pathways that regulate the differentiation of OPCs, and thus the myelination of CNS axons.
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Affiliation(s)
- Ben Emery
- Jungers Center for Neurosciences Research, Department of Neurology, Oregon Health & Science University, Portland, Oregon 97239, USA
| | - Teresa L Wood
- Department of Pharmacology, Physiology and Neuroscience, New Jersey Medical School, Rutgers University, Newark, New Jersey 07103, USA
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Marafie SK, Al-Mulla F, Abubaker J. mTOR: Its Critical Role in Metabolic Diseases, Cancer, and the Aging Process. Int J Mol Sci 2024; 25:6141. [PMID: 38892329 PMCID: PMC11173325 DOI: 10.3390/ijms25116141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Revised: 05/26/2024] [Accepted: 05/29/2024] [Indexed: 06/21/2024] Open
Abstract
The mammalian target of rapamycin (mTOR) is a pivotal regulator, integrating diverse environmental signals to control fundamental cellular functions, such as protein synthesis, cell growth, survival, and apoptosis. Embedded in a complex network of signaling pathways, mTOR dysregulation is implicated in the onset and progression of a range of human diseases, including metabolic disorders such as diabetes and cardiovascular diseases, as well as various cancers. mTOR also has a notable role in aging. Given its extensive biological impact, mTOR signaling is a prime therapeutic target for addressing these complex conditions. The development of mTOR inhibitors has proven advantageous in numerous research domains. This review delves into the significance of mTOR signaling, highlighting the critical components of this intricate network that contribute to disease. Additionally, it addresses the latest findings on mTOR inhibitors and their clinical implications. The review also emphasizes the importance of developing more effective next-generation mTOR inhibitors with dual functions to efficiently target the mTOR pathways. A comprehensive understanding of mTOR signaling will enable the development of effective therapeutic strategies for managing diseases associated with mTOR dysregulation.
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Affiliation(s)
- Sulaiman K. Marafie
- Biochemistry and Molecular Biology Department, Dasman Diabetes Institute, P.O. Box 1180, Dasman 15462, Kuwait
| | - Fahd Al-Mulla
- Department of Translational Research, Dasman Diabetes Institute, P.O. Box 1180, Dasman 15462, Kuwait;
| | - Jehad Abubaker
- Biochemistry and Molecular Biology Department, Dasman Diabetes Institute, P.O. Box 1180, Dasman 15462, Kuwait
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37
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Li K, Cao JF, Gong Y, Xiong L, Wu M, Qi Y, Ying X, Liu D, Ma X, Zhang X. Rapamycin improves the survival of epilepsy model cells by blocking phosphorylation of mTOR base on computer simulations and cellular experiments. Neurochem Int 2024; 176:105746. [PMID: 38641027 DOI: 10.1016/j.neuint.2024.105746] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Revised: 04/08/2024] [Accepted: 04/16/2024] [Indexed: 04/21/2024]
Abstract
PURPOSE Epilepsy is a chronic brain dysfunction characterized by recurrent epileptic seizures. Rapamycin is a naturally occurring macrolide from Streptomyces hygroscopicus, and rapamycin may provide a protective effect on the nervous system by affecting mTOR. Therefore, we investigated the pharmacologic mechanism of rapamycin treating epilepsy through bioinformatics analysis, cellular experiments and supercomputer simulation. METHODS Bioinformatics analysis was used to analyze targets of rapamycin treating epilepsy. We established epilepsy cell model by HT22 cells. RT-qPCR, WB and IF were used to verify the effects of rapamycin on mTOR at gene level and protein level. Computer simulations were used to model and evaluate the stability of rapamycin binding to mTOR protein. RESULTS Bioinformatics indicated mTOR played an essential role in signaling pathways of cell growth and cell metabolism. Cellular experiments showed that rapamycin could promote cell survival, and rapamycin did not have an effect on mRNA expression of mTOR. However, rapamycin was able to significantly inhibit the phosphorylation of mTOR at protein level. Computer simulations indicated that rapamycin was involved in the treatment of epilepsy through regulating phosphorylation of mTOR at protein level. CONCLUSION We found that rapamycin was capable of promoting the survival of epilepsy cells by inhibiting the phosphorylation of mTOR at protein level, and rapamycin did not have an effect on mRNA expression of mTOR. In addition to the traditional study that rapamycin affects mTORC1 complex by acting on FKBP12, this study found rapamycin could also directly block the phosphorylation of mTOR, therefore affecting the assembly of mTORC1 complex and mTOR signaling pathway.
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Affiliation(s)
- Kezhou Li
- College of Medicine, Southwest Jiaotong University, Chengdu, China; Pancreatic Surgery, West China Hospital of Sichuan University, Chengdu, China
| | - Jun-Feng Cao
- Chengdu Medical College, Chengdu, China; College of Medicine, Southwest Jiaotong University, Chengdu, China
| | | | - Li Xiong
- Chengdu Medical College, Chengdu, China
| | - Mei Wu
- Chengdu Medical College, Chengdu, China
| | - Yue Qi
- Chengdu Medical College, Chengdu, China
| | | | | | - Xuntai Ma
- Chengdu Medical College, Chengdu, China; The First Affiliated Hospital of Clinical Medical College of Chengdu Medical College, Chengdu, China.
| | - Xiao Zhang
- Chengdu Medical College, Chengdu, China.
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Onaka GM, de Carvalho MR, Onaka PK, Barbosa CM, Martinez PF, de Oliveira-Junior SA. Exercise, mTOR Activation, and Potential Impacts on the Liver in Rodents. BIOLOGY 2024; 13:362. [PMID: 38927242 PMCID: PMC11201249 DOI: 10.3390/biology13060362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Revised: 04/15/2024] [Accepted: 04/17/2024] [Indexed: 06/28/2024]
Abstract
The literature offers a consensus on the association between exercise training (ET) protocols based on the adequate parameters of intensity and frequency, and several adaptive alterations in the liver. Indeed, regular ET can reverse glucose and lipid metabolism disorders, especially from aerobic modalities, which can decrease intrahepatic fat formation. In terms of molecular mechanisms, the regulation of hepatic fat formation would be directly related to the modulation of the mechanistic target of rapamycin (mTOR), which would be stimulated by insulin signaling and Akt activation, from the following three different primary signaling pathways: (I) growth factor, (II) energy/ATP-sensitive, and (III) amino acid-sensitive signaling pathways, respectively. Hyperactivation of the Akt/mTORC1 pathway induces lipogenesis by regulating the action of sterol regulatory element binding protein-1 (SREBP-1). Exercise training interventions have been associated with multiple metabolic and tissue benefits. However, it is worth highlighting that the mTOR signaling in the liver in response to exercise interventions remains unclear. Hepatic adaptive alterations seem to be most outstanding when sustained by chronic interventions or high-intensity exercise protocols.
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Affiliation(s)
- Giuliano Moreto Onaka
- Graduate Program in Health and Development in the Midwest Region, Federal University of Mato Grosso do Sul—UFMS, Campo Grande 79070-900, MS, Brazil; (G.M.O.); (P.F.M.)
| | - Marianna Rabelo de Carvalho
- Graduate Program in Health and Development in the Midwest Region, Federal University of Mato Grosso do Sul—UFMS, Campo Grande 79070-900, MS, Brazil; (G.M.O.); (P.F.M.)
| | - Patricia Kubalaki Onaka
- Graduate Program in Education and Health, State University of Mato Grosso do Sul, Dourados 79804-970, MS, Brazil
| | - Claudiane Maria Barbosa
- Graduate Program in Movement Sciences, Federal University of Mato Grosso do Sul—UFMS, Campo Grande 79070-900, MS, Brazil;
| | - Paula Felippe Martinez
- Graduate Program in Health and Development in the Midwest Region, Federal University of Mato Grosso do Sul—UFMS, Campo Grande 79070-900, MS, Brazil; (G.M.O.); (P.F.M.)
- Graduate Program in Movement Sciences, Federal University of Mato Grosso do Sul—UFMS, Campo Grande 79070-900, MS, Brazil;
| | - Silvio Assis de Oliveira-Junior
- Graduate Program in Health and Development in the Midwest Region, Federal University of Mato Grosso do Sul—UFMS, Campo Grande 79070-900, MS, Brazil; (G.M.O.); (P.F.M.)
- Graduate Program in Movement Sciences, Federal University of Mato Grosso do Sul—UFMS, Campo Grande 79070-900, MS, Brazil;
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Ahmad MF, Ahmad FA, Hasan N, Alsayegh AA, Hakami O, Bantun F, Tasneem S, Alamier WM, Babalghith AO, Aldairi AF, Kambal N, Elbendary EY. Ganoderma lucidum: Multifaceted mechanisms to combat diabetes through polysaccharides and triterpenoids: A comprehensive review. Int J Biol Macromol 2024; 268:131644. [PMID: 38642691 DOI: 10.1016/j.ijbiomac.2024.131644] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2024] [Revised: 04/13/2024] [Accepted: 04/14/2024] [Indexed: 04/22/2024]
Abstract
Diabetes is a chronic metabolic disorder. Diabetes complications can affect many organs and systems in the body. Ganoderma lucidum (G. lucidum) contains various compounds that have been studied for their potential antidiabetic effects, including polysaccharides, triterpenoids (ganoderic acids, ganoderol B), proteoglycans, and G. lucidum extracts. G. lucidum polysaccharides (GLPs) and triterpenoids have been shown to act through distinct mechanisms, such as improving glucose metabolism, modulating the mitogen-activated protein kinase (MAPK) system, inhibiting the nuclear factor-kappa B (NF-κB) pathway, and protecting the pancreatic beta cells. While GLPs exhibit a significant role in controlling diabetic nephropathy and other associated complications. This review states the G. lucidum antidiabetic mechanisms of action and potential biologically active compounds that contribute to diabetes management and associated complications. To make G. lucidum an appropriate replacement for the treatment of diabetes with fewer side effects, more study is required to completely comprehend the number of physiologically active compounds present in it as well as the underlying cellular mechanisms that influence their effects on diabetes.
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Affiliation(s)
- Md Faruque Ahmad
- Department of Clinical Nutrition, College of Applied Medical Sciences, Jazan University, Jazan, Saudi Arabia.
| | - Fakhruddin Ali Ahmad
- Department of Basic and Applied Science, School of Engineering and Science, G.D Goenka University, Gurugram 122103, Haryana, India
| | - Nazim Hasan
- Department of Physical Sciences, Chemistry Division, College of Science, Jazan University, P. O. Box. 114, Jazan 45142, Saudi Arabia; Nanotechnology research unit, College of Science, Jazan University, P.O. Box. 114, Jazan 45142, Saudi Arabia.
| | - Abdulrahman A Alsayegh
- Department of Clinical Nutrition, College of Applied Medical Sciences, Jazan University, Jazan, Saudi Arabia
| | - Othman Hakami
- Department of Physical Sciences, Chemistry Division, College of Science, Jazan University, P. O. Box. 114, Jazan 45142, Saudi Arabia; Nanotechnology research unit, College of Science, Jazan University, P.O. Box. 114, Jazan 45142, Saudi Arabia
| | - Farkad Bantun
- Department of Microbiology and Parasitology, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Shadma Tasneem
- Department of Physical Sciences, Chemistry Division, College of Science, Jazan University, P. O. Box. 114, Jazan 45142, Saudi Arabia
| | - Waleed M Alamier
- Department of Physical Sciences, Chemistry Division, College of Science, Jazan University, P. O. Box. 114, Jazan 45142, Saudi Arabia; Nanotechnology research unit, College of Science, Jazan University, P.O. Box. 114, Jazan 45142, Saudi Arabia
| | - Ahmad O Babalghith
- Department of Medical Genetics, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Abdullah F Aldairi
- Department of Clinical Laboratory Sciences, Faculty of Applied Medical Sciences, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Nahla Kambal
- Department of Clinical Nutrition, College of Applied Medical Sciences, Jazan University, Jazan, Saudi Arabia
| | - Ehab Y Elbendary
- Department of Clinical Nutrition, College of Applied Medical Sciences, Jazan University, Jazan, Saudi Arabia
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Meuten TK, Dean GA, Thamm DH. Review: The PI3K-AKT-mTOR signal transduction pathway in canine cancer. Vet Pathol 2024; 61:339-356. [PMID: 37905509 DOI: 10.1177/03009858231207021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2023]
Abstract
Tumors in dogs and humans share many similar molecular and genetic features, incentivizing a better understanding of canine neoplasms not only for the purpose of treating companion animals, but also to facilitate research of spontaneously developing tumors with similar biologic behavior and treatment approaches in an immunologically competent animal model. Multiple tumor types of both species have similar dysregulation of signal transduction through phosphatidylinositol 3-kinase (PI3K), protein kinase B (PKB; AKT), and mechanistic target of rapamycin (mTOR), collectively known as the PI3K-AKT-mTOR pathway. This review aims to delineate the pertinent aspects of the PI3K-AKT-mTOR signaling pathway in health and in tumor development. It will then present a synopsis of current understanding of PI3K-AKT-mTOR signaling in important canine cancers and advancements in targeted inhibitors of this pathway.
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Radaszkiewicz KA, Sulcova M, Kohoutkova E, Harnos J. The role of prickle proteins in vertebrate development and pathology. Mol Cell Biochem 2024; 479:1199-1221. [PMID: 37358815 PMCID: PMC11116189 DOI: 10.1007/s11010-023-04787-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Accepted: 06/09/2023] [Indexed: 06/27/2023]
Abstract
Prickle is an evolutionarily conserved family of proteins exclusively associated with planar cell polarity (PCP) signalling. This signalling pathway provides directional and positional cues to eukaryotic cells along the plane of an epithelial sheet, orthogonal to both apicobasal and left-right axes. Through studies in the fruit fly Drosophila, we have learned that PCP signalling is manifested by the spatial segregation of two protein complexes, namely Prickle/Vangl and Frizzled/Dishevelled. While Vangl, Frizzled, and Dishevelled proteins have been extensively studied, Prickle has been largely neglected. This is likely because its role in vertebrate development and pathologies is still being explored and is not yet fully understood. The current review aims to address this gap by summarizing our current knowledge on vertebrate Prickle proteins and to cover their broad versatility. Accumulating evidence suggests that Prickle is involved in many developmental events, contributes to homeostasis, and can cause diseases when its expression and signalling properties are deregulated. This review highlights the importance of Prickle in vertebrate development, discusses the implications of Prickle-dependent signalling in pathology, and points out the blind spots or potential links regarding Prickle, which could be studied further.
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Affiliation(s)
- K A Radaszkiewicz
- Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, 62500, Czechia
| | - M Sulcova
- Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, 62500, Czechia
| | - E Kohoutkova
- Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, 62500, Czechia
| | - J Harnos
- Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, 62500, Czechia.
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Allard C, Miralpeix C, López-Gambero AJ, Cota D. mTORC1 in energy expenditure: consequences for obesity. Nat Rev Endocrinol 2024; 20:239-251. [PMID: 38225400 DOI: 10.1038/s41574-023-00934-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/29/2023] [Indexed: 01/17/2024]
Abstract
In eukaryotic cells, the mammalian target of rapamycin complex 1 (sometimes referred to as the mechanistic target of rapamycin complex 1; mTORC1) orchestrates cellular metabolism in response to environmental energy availability. As a result, at the organismal level, mTORC1 signalling regulates the intake, storage and use of energy by acting as a hub for the actions of nutrients and hormones, such as leptin and insulin, in different cell types. It is therefore unsurprising that deregulated mTORC1 signalling is associated with obesity. Strategies that increase energy expenditure offer therapeutic promise for the treatment of obesity. Here we review current evidence illustrating the critical role of mTORC1 signalling in the regulation of energy expenditure and adaptive thermogenesis through its various effects in neuronal circuits, adipose tissue and skeletal muscle. Understanding how mTORC1 signalling in one organ and cell type affects responses in other organs and cell types could be key to developing better, safer treatments targeting this pathway in obesity.
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Affiliation(s)
- Camille Allard
- University of Bordeaux, INSERM, Neurocentre Magendie, Bordeaux, France
| | | | | | - Daniela Cota
- University of Bordeaux, INSERM, Neurocentre Magendie, Bordeaux, France.
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Karalis V, Wood D, Teaney NA, Sahin M. The role of TSC1 and TSC2 proteins in neuronal axons. Mol Psychiatry 2024; 29:1165-1178. [PMID: 38212374 DOI: 10.1038/s41380-023-02402-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2023] [Revised: 12/20/2023] [Accepted: 12/22/2023] [Indexed: 01/13/2024]
Abstract
Tuberous Sclerosis Complex 1 and 2 proteins, TSC1 and TSC2 respectively, participate in a multiprotein complex with a crucial role for the proper development and function of the nervous system. This complex primarily acts as an inhibitor of the mechanistic target of rapamycin (mTOR) kinase, and mutations in either TSC1 or TSC2 cause a neurodevelopmental disorder called Tuberous Sclerosis Complex (TSC). Neurological manifestations of TSC include brain lesions, epilepsy, autism, and intellectual disability. On the cellular level, the TSC/mTOR signaling axis regulates multiple anabolic and catabolic processes, but it is not clear how these processes contribute to specific neurologic phenotypes. Hence, several studies have aimed to elucidate the role of this signaling pathway in neurons. Of particular interest are axons, as axonal defects are associated with severe neurocognitive impairments. Here, we review findings regarding the role of the TSC1/2 protein complex in axons. Specifically, we will discuss how TSC1/2 canonical and non-canonical functions contribute to the formation and integrity of axonal structure and function.
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Affiliation(s)
- Vasiliki Karalis
- Rosamund Stone Zander Translational Neuroscience Center, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA
- FM Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, 02115, USA
| | - Delaney Wood
- FM Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, 02115, USA
- Human Neuron Core, Boston Children's Hospital, Boston, MA, 02115, USA
| | - Nicole A Teaney
- Rosamund Stone Zander Translational Neuroscience Center, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA
- FM Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, 02115, USA
| | - Mustafa Sahin
- Rosamund Stone Zander Translational Neuroscience Center, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
- FM Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, 02115, USA.
- Human Neuron Core, Boston Children's Hospital, Boston, MA, 02115, USA.
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Kim H, Lebeau B, Papadopoli D, Jovanovic P, Russo M, Avizonis D, Morita M, Afzali F, Ursini-Siegel J, Postovit LM, Witcher M, Topisirovic I. MTOR modulation induces selective perturbations in histone methylation which influence the anti-proliferative effects of mTOR inhibitors. iScience 2024; 27:109188. [PMID: 38433910 PMCID: PMC10904987 DOI: 10.1016/j.isci.2024.109188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Revised: 01/11/2024] [Accepted: 02/06/2024] [Indexed: 03/05/2024] Open
Abstract
Emerging data suggest a significant cross-talk between metabolic and epigenetic programs. However, the relationship between the mechanistic target of rapamycin (mTOR), which is a pivotal metabolic regulator, and epigenetic modifications remains poorly understood. Our results show that mTORC1 activation caused by the abrogation of its negative regulator tuberous sclerosis complex 2 (TSC2) coincides with increased levels of the histone modification H3K27me3 but not H3K4me3 or H3K9me3. This selective H3K27me3 induction was mediated via 4E-BP-dependent increase in EZH2 protein levels. Surprisingly, mTOR inhibition also selectively induced H3K27me3. This was independent of TSC2, and was paralleled by reduced EZH2 and increased EZH1 protein levels. Notably, the ability of mTOR inhibitors to induce H3K27me3 levels was positively correlated with their anti-proliferative effects. Collectively, our findings demonstrate that both activation and inhibition of mTOR selectively increase H3K27me3 by distinct mechanisms, whereby the induction of H3K27me3 may potentiate the anti-proliferative effects of mTOR inhibitors.
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Affiliation(s)
- HaEun Kim
- Department of Experimental Medicine, McGill University, Montreal, QC H3A 0G4, Canada
- Lady Davis Institute, SMBD JGH, McGill University, Montreal, QC H3T 1E2, Canada
| | - Benjamin Lebeau
- Department of Experimental Medicine, McGill University, Montreal, QC H3A 0G4, Canada
- Lady Davis Institute, SMBD JGH, McGill University, Montreal, QC H3T 1E2, Canada
- School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore
| | - David Papadopoli
- Lady Davis Institute, SMBD JGH, McGill University, Montreal, QC H3T 1E2, Canada
- Gerald Bronfman Department of Oncology, McGill University, Montreal, QC H3A 0G4, Canada
| | - Predrag Jovanovic
- Department of Experimental Medicine, McGill University, Montreal, QC H3A 0G4, Canada
- Lady Davis Institute, SMBD JGH, McGill University, Montreal, QC H3T 1E2, Canada
| | - Mariana Russo
- Goodman Cancer Research Centre, Montréal, QC H3A 1A3, Canada
| | - Daina Avizonis
- Goodman Cancer Research Centre, Montréal, QC H3A 1A3, Canada
| | - Masahiro Morita
- Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
- Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
| | - Farzaneh Afzali
- Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON K7L 3N6, Canada
| | - Josie Ursini-Siegel
- Department of Experimental Medicine, McGill University, Montreal, QC H3A 0G4, Canada
- Lady Davis Institute, SMBD JGH, McGill University, Montreal, QC H3T 1E2, Canada
- Gerald Bronfman Department of Oncology, McGill University, Montreal, QC H3A 0G4, Canada
- Department of Biochemistry, McGill University, Montreal, QC H3A 0G4, Canada
| | - Lynne-Marie Postovit
- Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON K7L 3N6, Canada
| | - Michael Witcher
- Department of Experimental Medicine, McGill University, Montreal, QC H3A 0G4, Canada
- Lady Davis Institute, SMBD JGH, McGill University, Montreal, QC H3T 1E2, Canada
- Gerald Bronfman Department of Oncology, McGill University, Montreal, QC H3A 0G4, Canada
| | - Ivan Topisirovic
- Department of Experimental Medicine, McGill University, Montreal, QC H3A 0G4, Canada
- Lady Davis Institute, SMBD JGH, McGill University, Montreal, QC H3T 1E2, Canada
- Gerald Bronfman Department of Oncology, McGill University, Montreal, QC H3A 0G4, Canada
- Department of Biochemistry, McGill University, Montreal, QC H3A 0G4, Canada
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45
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Jhanwar-Uniyal M, Zeller SL, Spirollari E, Das M, Hanft SJ, Gandhi CD. Discrete Mechanistic Target of Rapamycin Signaling Pathways, Stem Cells, and Therapeutic Targets. Cells 2024; 13:409. [PMID: 38474373 PMCID: PMC10930964 DOI: 10.3390/cells13050409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Revised: 02/14/2024] [Accepted: 02/22/2024] [Indexed: 03/14/2024] Open
Abstract
The mechanistic target of rapamycin (mTOR) is a serine/threonine kinase that functions via its discrete binding partners to form two multiprotein complexes, mTOR complex 1 and 2 (mTORC1 and mTORC2). Rapamycin-sensitive mTORC1, which regulates protein synthesis and cell growth, is tightly controlled by PI3K/Akt and is nutrient-/growth factor-sensitive. In the brain, mTORC1 is also sensitive to neurotransmitter signaling. mTORC2, which is modulated by growth factor signaling, is associated with ribosomes and is insensitive to rapamycin. mTOR regulates stem cell and cancer stem cell characteristics. Aberrant Akt/mTOR activation is involved in multistep tumorigenesis in a variety of cancers, thereby suggesting that the inhibition of mTOR may have therapeutic potential. Rapamycin and its analogues, known as rapalogues, suppress mTOR activity through an allosteric mechanism that only suppresses mTORC1, albeit incompletely. ATP-catalytic binding site inhibitors are designed to inhibit both complexes. This review describes the regulation of mTOR and the targeting of its complexes in the treatment of cancers, such as glioblastoma, and their stem cells.
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Affiliation(s)
- Meena Jhanwar-Uniyal
- Department of Neurosurgery, Westchester Medical Center, New York Medical College, Valhalla, NY 10595, USA
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Kommaddi RP, Gowaikar R, P A H, Diwakar L, Singh K, Mondal A. Akt activation ameliorates deficits in hippocampal-dependent memory and activity-dependent synaptic protein synthesis in an Alzheimer's disease mouse model. J Biol Chem 2024; 300:105619. [PMID: 38182004 PMCID: PMC10839450 DOI: 10.1016/j.jbc.2023.105619] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Revised: 12/22/2023] [Accepted: 12/24/2023] [Indexed: 01/07/2024] Open
Abstract
Protein kinase-B (Akt) and the mechanistic target of rapamycin (mTOR) signaling pathways are implicated in Alzheimer's disease (AD) pathology. Akt/mTOR signaling pathways, activated by external inputs, enable new protein synthesis at the synapse and synaptic plasticity. The molecular mechanisms impeding new protein synthesis at the synapse in AD pathogenesis remain elusive. Here, we aimed to understand the molecular mechanisms prior to the manifestation of histopathological hallmarks by characterizing Akt1/mTOR signaling cascades and new protein synthesis in the hippocampus of WT and amyloid precursor protein/presenilin-1 (APP/PS1) male mice. Intriguingly, compared to those in WT mice, we found significant decreases in pAkt1, pGSK3β, pmTOR, pS6 ribosomal protein, and p4E-BP1 levels in both post nuclear supernatant and synaptosomes isolated from the hippocampus of one-month-old (presymptomatic) APP/PS1 mice. In synaptoneurosomes prepared from the hippocampus of presymptomatic APP/PS1 mice, activity-dependent protein synthesis at the synapse was impaired and this deficit was sustained in young adults. In hippocampal neurons from C57BL/6 mice, downregulation of Akt1 precluded synaptic activity-dependent protein synthesis at the dendrites but not in the soma. In three-month-old APP/PS1 mice, Akt activator (SC79) administration restored deficits in memory recall and activity-dependent synaptic protein synthesis. C57BL/6 mice administered with an Akt inhibitor (MK2206) resulted in memory recall deficits compared to those treated with vehicle. We conclude that dysregulation of Akt1/mTOR and its downstream signaling molecules in the hippocampus contribute to memory recall deficits and loss of activity-dependent synaptic protein synthesis. In AD mice, however, Akt activation ameliorates deficits in memory recall and activity-dependent synaptic protein synthesis.
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Affiliation(s)
| | - Ruturaj Gowaikar
- Centre for Neuroscience, Indian Institute of Science, Bangalore, India
| | - Haseena P A
- Centre for Brain Research, Indian Institute of Science, Bangalore, India; Manipal Academy of Higher Education, Manipal, India
| | - Latha Diwakar
- Centre for Brain Research, Indian Institute of Science, Bangalore, India
| | - Kunal Singh
- Centre for Neuroscience, Indian Institute of Science, Bangalore, India
| | - Amrita Mondal
- Centre for Brain Research, Indian Institute of Science, Bangalore, India
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Shin HC, Kim J, Park SR, Choi BH. mTOR Plays an Important Role in the Stemness of Human Fetal Cartilage Progenitor Cells (hFCPCs). Tissue Eng Regen Med 2024; 21:309-318. [PMID: 37812329 PMCID: PMC10825109 DOI: 10.1007/s13770-023-00598-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Revised: 08/18/2023] [Accepted: 09/07/2023] [Indexed: 10/10/2023] Open
Abstract
BACKGROUND Mammalian target of rapamycin (mTOR) is known to regulate self-renewal ability and potency of embryonic stem cells (ESCs) and adult stem cells in opposite manners. However, its effects vary even among adult stem cells and are not reported in fetal stem/progenitor cells. This study investigated the role of mTOR in the function of human fetal cartilage-derived progenitor cells (hFCPCs). METHODS mTOR activity in hFCPCs was first examined via the level of phosphor-mTOR until passage 19, together with doubling time of cells and senescence-associated b-galactosidase (SA-bGal). Then, the effect of 100 nM rapamycin, the inhibitor of mTOR, was investigated on self-renewal ability, proliferation rate and osteogenic/adipogenic potential of hFCPCs in vitro. Expression of stemness genes (Oct-4, Sox2 and Nanog) and cell cycle regulators (CDK4 and Cyclin D1) was measured at mRNA or protein levels. RESULTS mTOR activity was maintained constantly at high levels in hFCPCs until passage 19, while their proliferation rate was decreasing from 48 h at passage 13 to 70 h at passage 9 and senescent cells were observed at passage 18 (8.3 ± 1.2%) and 19 (15.6 ± 1.9%). Inhibition of mTOR in hFCPCs impaired their colony forming frequency (CFU-F) by 4 folds, while showing no change in their doubling time and expression of CDK4 and Cyclin D1. Upon mTOR inhibition, Oct4 expression decreased by 2 folds and 4 folds at the mRNA and protein levels, respectively, while that of Sox2 and Nanog did not change significantly. Finally, mTOR inhibition reduced osteogenic and adipogenic differentiation of hFCPCs in vitro. CONCLUSION This study has shown that mTOR plays an important role in the self-renewal ability of hFCPCS but not in their proliferation, The effect of mTOR appears to be associated with Oct-4 expression and important in the osteogenic and adipogenic differentiation ability of hFCPCs.
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Affiliation(s)
- Him-Cha Shin
- Department of Physiology and Biophysics, Inha University College of Medicine, 100 Inha-ro, Michuhol-gu, Incheon, 22212, South Korea
| | - Jiyoung Kim
- Department of Biomedical Sciences, Inha University College of Medicine, 100 Inha-ro, Michuhol-gu, Incheon, 22212, South Korea
| | - So Ra Park
- Department of Physiology and Biophysics, Inha University College of Medicine, 100 Inha-ro, Michuhol-gu, Incheon, 22212, South Korea
| | - Byung Hyune Choi
- Department of Biomedical Sciences, Inha University College of Medicine, 100 Inha-ro, Michuhol-gu, Incheon, 22212, South Korea.
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Ragupathi A, Kim C, Jacinto E. The mTORC2 signaling network: targets and cross-talks. Biochem J 2024; 481:45-91. [PMID: 38270460 PMCID: PMC10903481 DOI: 10.1042/bcj20220325] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Revised: 11/29/2023] [Accepted: 12/18/2023] [Indexed: 01/26/2024]
Abstract
The mechanistic target of rapamycin, mTOR, controls cell metabolism in response to growth signals and stress stimuli. The cellular functions of mTOR are mediated by two distinct protein complexes, mTOR complex 1 (mTORC1) and mTORC2. Rapamycin and its analogs are currently used in the clinic to treat a variety of diseases and have been instrumental in delineating the functions of its direct target, mTORC1. Despite the lack of a specific mTORC2 inhibitor, genetic studies that disrupt mTORC2 expression unravel the functions of this more elusive mTOR complex. Like mTORC1 which responds to growth signals, mTORC2 is also activated by anabolic signals but is additionally triggered by stress. mTORC2 mediates signals from growth factor receptors and G-protein coupled receptors. How stress conditions such as nutrient limitation modulate mTORC2 activation to allow metabolic reprogramming and ensure cell survival remains poorly understood. A variety of downstream effectors of mTORC2 have been identified but the most well-characterized mTORC2 substrates include Akt, PKC, and SGK, which are members of the AGC protein kinase family. Here, we review how mTORC2 is regulated by cellular stimuli including how compartmentalization and modulation of complex components affect mTORC2 signaling. We elaborate on how phosphorylation of its substrates, particularly the AGC kinases, mediates its diverse functions in growth, proliferation, survival, and differentiation. We discuss other signaling and metabolic components that cross-talk with mTORC2 and the cellular output of these signals. Lastly, we consider how to more effectively target the mTORC2 pathway to treat diseases that have deregulated mTOR signaling.
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Affiliation(s)
- Aparna Ragupathi
- Department of Biochemistry and Molecular Biology, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, U.S.A
| | - Christian Kim
- Department of Biochemistry and Molecular Biology, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, U.S.A
| | - Estela Jacinto
- Department of Biochemistry and Molecular Biology, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, U.S.A
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Rahman M, Nguyen TM, Lee GJ, Kim B, Park MK, Lee CH. Unraveling the Role of Ras Homolog Enriched in Brain (Rheb1 and Rheb2): Bridging Neuronal Dynamics and Cancer Pathogenesis through Mechanistic Target of Rapamycin Signaling. Int J Mol Sci 2024; 25:1489. [PMID: 38338768 PMCID: PMC10855792 DOI: 10.3390/ijms25031489] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Revised: 01/14/2024] [Accepted: 01/17/2024] [Indexed: 02/12/2024] Open
Abstract
Ras homolog enriched in brain (Rheb1 and Rheb2), small GTPases, play a crucial role in regulating neuronal activity and have gained attention for their implications in cancer development, particularly in breast cancer. This study delves into the intricate connection between the multifaceted functions of Rheb1 in neurons and cancer, with a specific focus on the mTOR pathway. It aims to elucidate Rheb1's involvement in pivotal cellular processes such as proliferation, apoptosis resistance, migration, invasion, metastasis, and inflammatory responses while acknowledging that Rheb2 has not been extensively studied. Despite the recognized associations, a comprehensive understanding of the intricate interplay between Rheb1 and Rheb2 and their roles in both nerve and cancer remains elusive. This review consolidates current knowledge regarding the impact of Rheb1 on cancer hallmarks and explores the potential of Rheb1 as a therapeutic target in cancer treatment. It emphasizes the necessity for a deeper comprehension of the molecular mechanisms underlying Rheb1-mediated oncogenic processes, underscoring the existing gaps in our understanding. Additionally, the review highlights the exploration of Rheb1 inhibitors as a promising avenue for cancer therapy. By shedding light on the complicated roles between Rheb1/Rheb2 and cancer, this study provides valuable insights to the scientific community. These insights are instrumental in guiding the identification of novel targets and advancing the development of effective therapeutic strategies for treating cancer.
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Affiliation(s)
- Mostafizur Rahman
- College of Pharmacy, Dongguk University, Seoul 04620, Republic of Korea; (M.R.); (G.J.L.)
| | - Tuan Minh Nguyen
- College of Pharmacy, Dongguk University, Seoul 04620, Republic of Korea; (M.R.); (G.J.L.)
| | - Gi Jeong Lee
- College of Pharmacy, Dongguk University, Seoul 04620, Republic of Korea; (M.R.); (G.J.L.)
| | - Boram Kim
- College of Pharmacy, Dongguk University, Seoul 04620, Republic of Korea; (M.R.); (G.J.L.)
| | - Mi Kyung Park
- Department of BioHealthcare, Hwasung Medi-Science University, Hwaseong-si 18274, Republic of Korea
| | - Chang Hoon Lee
- College of Pharmacy, Dongguk University, Seoul 04620, Republic of Korea; (M.R.); (G.J.L.)
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Nuñez Y, Vera S, Baeza V, Gonzalez-Pecchi V. NSD3 in Cancer: Unraveling Methyltransferase-Dependent and Isoform-Specific Functions. Int J Mol Sci 2024; 25:944. [PMID: 38256018 PMCID: PMC10815784 DOI: 10.3390/ijms25020944] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 12/29/2023] [Accepted: 01/04/2024] [Indexed: 01/24/2024] Open
Abstract
NSD3 (nuclear receptor-binding SET domain protein 3) is a member of the NSD histone methyltransferase family of proteins. In recent years, it has been identified as a potential oncogene in certain types of cancer. The NSD3 gene encodes three isoforms, the long version (NSD3L), a short version (NSD3S) and the WHISTLE isoforms. Importantly, the NSD3S isoform corresponds to the N-terminal region of the full-length protein, lacking the methyltransferase domain. The chromosomal location of NSD3 is frequently amplified across cancer types, such as breast, lung, and colon, among others. Recently, this amplification has been correlated to a chromothripsis event, that could explain the different NSD3 alterations found in cancer. The fusion proteins containing NSD3 have also been reported in leukemia (NSD3-NUP98), and in NUT (nuclear protein of the testis) midline carcinoma (NSD3-NUT). Its role as an oncogene has been described by modulating different cancer pathways through its methyltransferase activity, or the short isoform of the protein, through protein interactions. Specifically, in this review we will focus on the functions that have been characterized as methyltransferase dependent, and those that have been correlated with the expression of the NSD3S isoform. There is evidence that both the NSD3L and NSD3S isoforms are relevant for cancer progression, establishing NSD3 as a therapeutic target. However, further functional studies are needed to differentiate NSD3 oncogenic activity as dependent or independent of the catalytic domain of the protein, as well as the contribution of each isoform and its clinical significance in cancer progression.
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Affiliation(s)
- Yanara Nuñez
- Biomedical Science Research Laboratory, Department of Basic Sciences, Faculty of Medicine, Universidad Católica de la Santísima Concepción, Concepción 4090541, Chile; (Y.N.); (S.V.); (V.B.)
- Biochemistry, Faculty of Pharmacy, Universidad de Concepción, Concepción 4070383, Chile
| | - Sebastian Vera
- Biomedical Science Research Laboratory, Department of Basic Sciences, Faculty of Medicine, Universidad Católica de la Santísima Concepción, Concepción 4090541, Chile; (Y.N.); (S.V.); (V.B.)
| | - Victor Baeza
- Biomedical Science Research Laboratory, Department of Basic Sciences, Faculty of Medicine, Universidad Católica de la Santísima Concepción, Concepción 4090541, Chile; (Y.N.); (S.V.); (V.B.)
| | - Valentina Gonzalez-Pecchi
- Biomedical Science Research Laboratory, Department of Basic Sciences, Faculty of Medicine, Universidad Católica de la Santísima Concepción, Concepción 4090541, Chile; (Y.N.); (S.V.); (V.B.)
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