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1
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Upadia J, Liu J, Bier C, Chenevert M, Li Y. Diverse Clinical Presentation of RAC1-Related Intellectual Developmental Disorder. Am J Med Genet A 2025; 197:e63991. [PMID: 39838818 DOI: 10.1002/ajmg.a.63991] [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: 09/09/2024] [Revised: 12/20/2024] [Accepted: 01/03/2025] [Indexed: 01/23/2025]
Abstract
RAC1 encodes the protein RAS-related C3 Botulinum Toxin Substrate 1 (RAC1), which plays a pivotal role in various cellular functions. Pathogenic variants in RAC1 are linked to the rare intellectual developmental disorder, autosomal-dominant 48 (MRD48). We present one case with typical phenotype and two cases with a mild phenotype. This report expands the phenotypic spectrum of MRD48.
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Affiliation(s)
- Jariya Upadia
- Hayward Genetics Center, Tulane University School of Medicine, New Orleans, Louisiana, USA
- Department of Pediatrics, Tulane University School of Medicine, New Orleans, Louisiana, USA
| | - Jiao Liu
- Hayward Genetics Center, Tulane University School of Medicine, New Orleans, Louisiana, USA
- Department of Pediatrics, Tulane University School of Medicine, New Orleans, Louisiana, USA
| | - Caide Bier
- Hayward Genetics Center, Tulane University School of Medicine, New Orleans, Louisiana, USA
- Department of Pediatrics, Tulane University School of Medicine, New Orleans, Louisiana, USA
| | - Madeline Chenevert
- Hayward Genetics Center, Tulane University School of Medicine, New Orleans, Louisiana, USA
- Department of Pediatrics, Tulane University School of Medicine, New Orleans, Louisiana, USA
| | - Yuwen Li
- Hayward Genetics Center, Tulane University School of Medicine, New Orleans, Louisiana, USA
- Department of Pediatrics, Tulane University School of Medicine, New Orleans, Louisiana, USA
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2
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Zhang Y, Ma Y, Zhang K, Wang Y, Sun X, Kan C, Han F. KRAS Mutations in Cancer: From Molecular Insights to Therapeutic Strategies. Am J Clin Oncol 2025:00000421-990000000-00275. [PMID: 40167108 DOI: 10.1097/coc.0000000000001192] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/02/2025]
Abstract
The global burden of cancer remains a major public health challenge, with Kirsten rat sarcoma viral oncogene homolog (KRAS) emerging as the most common mutated oncogene across diverse malignancies. Once considered "undruggable" due to its unique structure, KRAS has garnered intense research focus, resulting in significant advancements. This paper aims to review recent developments in our understanding of KRAS biology, including its structural and functional aspects, and to explore the latest insights into its mutations across various cancer types. Emphasis is placed on prognosis, predictive roles, and emerging therapeutic strategies targeting KRAS. This review aspires to deepen our comprehension of KRAS and potentially enhance treatment outcomes for cancer patients harboring KRAS mutations in the future.
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Affiliation(s)
- Yuanzhu Zhang
- Department of Endocrinology and Metabolism, Shandong Provincial Key Medical and Health Discipline of Endocrinology and Laboratory of Endocrinology and Metabolic Diseases, Clinical Research Center
- Department of Pathology, Affiliated Hospital of Shandong Second Medical University, Weifang, China
| | - Yujie Ma
- Department of Endocrinology and Metabolism, Shandong Provincial Key Medical and Health Discipline of Endocrinology and Laboratory of Endocrinology and Metabolic Diseases, Clinical Research Center
| | - Kexin Zhang
- Department of Endocrinology and Metabolism, Shandong Provincial Key Medical and Health Discipline of Endocrinology and Laboratory of Endocrinology and Metabolic Diseases, Clinical Research Center
| | - Yuqun Wang
- Department of Endocrinology and Metabolism, Shandong Provincial Key Medical and Health Discipline of Endocrinology and Laboratory of Endocrinology and Metabolic Diseases, Clinical Research Center
| | - Xiaodong Sun
- Department of Endocrinology and Metabolism, Shandong Provincial Key Medical and Health Discipline of Endocrinology and Laboratory of Endocrinology and Metabolic Diseases, Clinical Research Center
| | - Chengxia Kan
- Department of Endocrinology and Metabolism, Shandong Provincial Key Medical and Health Discipline of Endocrinology and Laboratory of Endocrinology and Metabolic Diseases, Clinical Research Center
| | - Fang Han
- Department of Endocrinology and Metabolism, Shandong Provincial Key Medical and Health Discipline of Endocrinology and Laboratory of Endocrinology and Metabolic Diseases, Clinical Research Center
- Department of Pathology, Affiliated Hospital of Shandong Second Medical University, Weifang, China
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3
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Stojchevski R, Sutanto EA, Sutanto R, Hadzi-Petrushev N, Mladenov M, Singh SR, Sinha JK, Ghosh S, Yarlagadda B, Singh KK, Verma P, Sengupta S, Bhaskar R, Avtanski D. Translational Advances in Oncogene and Tumor-Suppressor Gene Research. Cancers (Basel) 2025; 17:1008. [PMID: 40149342 PMCID: PMC11940485 DOI: 10.3390/cancers17061008] [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: 02/10/2025] [Revised: 03/10/2025] [Accepted: 03/15/2025] [Indexed: 03/29/2025] Open
Abstract
Cancer, characterized by the uncontrolled proliferation of cells, is one of the leading causes of death globally, with approximately one in five people developing the disease in their lifetime. While many driver genes were identified decades ago, and most cancers can be classified based on morphology and progression, there is still a significant gap in knowledge about genetic aberrations and nuclear DNA damage. The study of two critical groups of genes-tumor suppressors, which inhibit proliferation and promote apoptosis, and oncogenes, which regulate proliferation and survival-can help to understand the genomic causes behind tumorigenesis, leading to more personalized approaches to diagnosis and treatment. Aberration of tumor suppressors, which undergo two-hit and loss-of-function mutations, and oncogenes, activated forms of proto-oncogenes that experience one-hit and gain-of-function mutations, are responsible for the dysregulation of key signaling pathways that regulate cell division, such as p53, Rb, Ras/Raf/ERK/MAPK, PI3K/AKT, and Wnt/β-catenin. Modern breakthroughs in genomics research, like next-generation sequencing, have provided efficient strategies for mapping unique genomic changes that contribute to tumor heterogeneity. Novel therapeutic approaches have enabled personalized medicine, helping address genetic variability in tumor suppressors and oncogenes. This comprehensive review examines the molecular mechanisms behind tumor-suppressor genes and oncogenes, the key signaling pathways they regulate, epigenetic modifications, tumor heterogeneity, and the drug resistance mechanisms that drive carcinogenesis. Moreover, the review explores the clinical application of sequencing techniques, multiomics, diagnostic procedures, pharmacogenomics, and personalized treatment and prevention options, discussing future directions for emerging technologies.
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Affiliation(s)
- Radoslav Stojchevski
- Friedman Diabetes Institute, Lenox Hill Hospital, Northwell Health, New York, NY 10022, USA;
- Feinstein Institutes for Medical Research, Manhasset, NY 11030, USA
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY 11549, USA
| | - Edward Agus Sutanto
- CUNY School of Medicine, The City College of New York, 160 Convent Avenue, New York, NY 10031, USA;
| | - Rinni Sutanto
- New York Institute of Technology College of Osteopathic Medicine, Glen Head, NY 11545, USA;
| | - Nikola Hadzi-Petrushev
- Faculty of Natural Sciences and Mathematics, Institute of Biology, Ss. Cyril and Methodius University, 1000 Skopje, North Macedonia; (N.H.-P.)
| | - Mitko Mladenov
- Faculty of Natural Sciences and Mathematics, Institute of Biology, Ss. Cyril and Methodius University, 1000 Skopje, North Macedonia; (N.H.-P.)
| | - Sajal Raj Singh
- GloNeuro, Sector 107, Vishwakarma Road, Noida 201301, Uttar Pradesh, India (J.K.S.)
| | - Jitendra Kumar Sinha
- GloNeuro, Sector 107, Vishwakarma Road, Noida 201301, Uttar Pradesh, India (J.K.S.)
| | - Shampa Ghosh
- GloNeuro, Sector 107, Vishwakarma Road, Noida 201301, Uttar Pradesh, India (J.K.S.)
| | | | - Krishna Kumar Singh
- Symbiosis Centre for Information Technology (SCIT), Rajiv Gandhi InfoTech Park, Hinjawadi, Pune 411057, Maharashtra, India;
| | - Prashant Verma
- School of Management, BML Munjal University, NH8, Sidhrawali, Gurugram 122413, Haryana, India
| | - Sonali Sengupta
- Department of Gastroenterology, All India Institute of Medical Sciences (AIIMS), New Delhi 110029, India
| | - Rakesh Bhaskar
- School of Chemical Engineering, Yeungnam University, Gyeongsan 38541, Republic of Korea
- Research Institute of Cell Culture, Yeungnam University, Gyeongsan 38541, Republic of Korea
| | - Dimiter Avtanski
- Friedman Diabetes Institute, Lenox Hill Hospital, Northwell Health, New York, NY 10022, USA;
- Feinstein Institutes for Medical Research, Manhasset, NY 11030, USA
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY 11549, USA
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4
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Carrillo MP, Piña B, Vila-Costa M, Barata C. Molecular mechanisms that regulate scopolamine effects on inducible fish antipredation responses in Daphnia magna. Comp Biochem Physiol C Toxicol Pharmacol 2025; 289:110116. [PMID: 39725184 DOI: 10.1016/j.cbpc.2024.110116] [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: 11/04/2024] [Revised: 12/13/2024] [Accepted: 12/21/2024] [Indexed: 12/28/2024]
Abstract
Daphnia's antipredator responses are regulated largely by the nervous system, making these responses particularly susceptible to compounds that impact neurodevelopmental or neurofunctional processes. This study aimed to determine the molecular pathways involved in modulating the effects of scopolamine on inducible antipredation responses triggered by fish kairomones. We used two clones showing two contrasting responses. The positive phototactic clone 85 responds strongly to fish kairomones showing a marked negative phototactism and higher developmental rates. Consistently, the negative phototactic clone F shows the opposite behavior to the same stimuli. Adults of both clones were exposed to fish kairomones, scopolamine alone and a mixture of both. Scopolamine is a muscarine antagonist able to mimic fish kairomones inducible behavioral responses in both clones, while affecting differently morphological and life-history traits. Whole transcriptomic Illumina analyses indicated a greater number of de-regulated genes of the fish kairomone sensitive clone 85 (1650) compared to the F one (1138), which were grouped in four clusters (two per clone). The mixture of scopolamine and fish kairomone treatments on gene transcription was additive in both clones, indicating similar modes of action. Most enriched metabolic routes were related with neurological pathways and regulation of cell proliferation/differentiation. Our results indicate that fish kairomones and scopolamine deregulate not only neurological signaling pathways but also cell differentiation and proliferation pathways, which are linked to the observed behavioral responses as well as the developmental, morphological, and reproductive effects.
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Affiliation(s)
- María Paula Carrillo
- Institute of Environmental Assessment and Water Research (IDAEA-CSIC), Barcelona, Spain
| | - Benjamín Piña
- Institute of Environmental Assessment and Water Research (IDAEA-CSIC), Barcelona, Spain
| | - Maria Vila-Costa
- Institute of Environmental Assessment and Water Research (IDAEA-CSIC), Barcelona, Spain
| | - Carlos Barata
- Institute of Environmental Assessment and Water Research (IDAEA-CSIC), Barcelona, Spain.
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5
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Hu Z, Martí J. Unraveling atomic-scale mechanisms of GDP extraction catalyzed by SOS1 in KRAS-G12 and KRAS-D12 oncogenes. Comput Biol Med 2025; 186:109599. [PMID: 39731920 DOI: 10.1016/j.compbiomed.2024.109599] [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: 10/02/2024] [Revised: 12/16/2024] [Accepted: 12/17/2024] [Indexed: 12/30/2024]
Abstract
The guanine exchange factor SOS1 plays a pivotal role in the positive feedback regulation of the KRAS signaling pathway. Recently, the regulation of KRAS-SOS1 interactions and KRAS downstream effector proteins has emerged as a key focus in the development of therapies targeting KRAS-driven cancers. However, the detailed dynamic mechanisms underlying SOS1-catalyzed GDP extraction and the impact of KRAS mutations remain largely unexplored. In this study, we unveil and describe in atomic detail the primary mechanisms by which SOS1 facilitates GDP extraction from KRAS oncogenes. For GDP-bound wild-type KRAS (KRAS-G12), four critical amino acids (Lys811, Glu812, Lys939, and Glu942) are identified as essential for the catalytic function of SOS1. Notably, the KRAS-G12D mutation (KRAS-D12) significantly accelerates the rate of GDP extraction. The molecular basis of this enhancement are attributed to hydrogen bonding interactions between the mutant residue Asp12 and a positively charged pocket in the intrinsically disordered region (residues 807-818), comprising Ser807, Trp809, Thr810, and Lys811. These findings provide novel insights into SOS1-KRAS interactions and offer a foundation for developing anti-cancer strategies aimed at disrupting these mechanisms.
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Affiliation(s)
- Zheyao Hu
- Department of Physics, Polytechnic University of Catalonia-Barcelona Tech, B4-B5 Northern Campus UPC, Barcelona, 08034, Catalonia, Spain
| | - Jordi Martí
- Department of Physics, Polytechnic University of Catalonia-Barcelona Tech, B4-B5 Northern Campus UPC, Barcelona, 08034, Catalonia, Spain.
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6
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Sabek Y, Zhang Z, Nishibe N, Maruta S. Ionic control of small GTPase HRas using calmodulin. J Biochem 2025; 177:153-161. [PMID: 39696662 DOI: 10.1093/jb/mvae089] [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: 08/01/2024] [Revised: 12/04/2024] [Accepted: 12/05/2024] [Indexed: 12/20/2024] Open
Abstract
HRas is a small GTPase that plays physiologically important roles in various intracellular signal transduction processes, such as cell growth and proliferation. The structure and action mechanisms of HRas have been well characterized, leading to its widespread use as a molecular switch in bionanomachines. Calmodulin (CaM), a calcium ion-binding protein, acts as an ion-binding molecular switch and activates the target enzymes. We previously demonstrated that the fusion protein of HRas (M13-HRas) with the CaM target peptide M13 at the N-terminus of HRas exhibits reversible regulation of GTPase activity and the interaction between M13-HRas and the downstream signalling factor Raf by calcium ions with CaM. In this study, we prepared two new HRas fusion proteins with the M13 peptide at the C-terminus (HRas-M13) and both termini (M13-HRas-M13) of HRas and analysed the calcium-dependent regulation of HRas function. M13-HRas-M13 more efficiently controlled GTPase, interaction with Raf and the HRas regulator GEF by calcium ions with CaM.
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Affiliation(s)
- Yassine Sabek
- Department of Biosciences, Graduate School of Science and Engineering, Soka University, 1-236 Tangi-cho, Hachioji, Tokyo 192-8577, Japan
| | - Ziyun Zhang
- Department of Biosciences, Graduate School of Science and Engineering, Soka University, 1-236 Tangi-cho, Hachioji, Tokyo 192-8577, Japan
| | - Nobuyuki Nishibe
- Department of Biosciences, Graduate School of Science and Engineering, Soka University, 1-236 Tangi-cho, Hachioji, Tokyo 192-8577, Japan
| | - Shinsaku Maruta
- Department of Biosciences, Graduate School of Science and Engineering, Soka University, 1-236 Tangi-cho, Hachioji, Tokyo 192-8577, Japan
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7
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Ammour Y, Nikolaeva E, Sagimbaeva O, Shamsutdinov P, Astapenko A, Zhelaeva Y, Gavrilova M, Susova O, Mitrofanov A, Bekyashev A, Nasedkina T, Svitich O, Faizuloev E, Zverev V. Human Melanoma and Glioblastoma Cells Express Cathepsins Supporting Reovirus Moscow Strain Infection. Viruses 2024; 16:1944. [PMID: 39772250 PMCID: PMC11680368 DOI: 10.3390/v16121944] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Revised: 12/16/2024] [Accepted: 12/17/2024] [Indexed: 01/11/2025] Open
Abstract
This study evaluates the oncolytic potential of the Moscow strain of reovirus against human metastatic melanoma and glioblastoma cells. The Moscow strain effectively infects and replicates within human melanoma cell lines and primary glioblastoma cells, while sparing non-malignant human cells. Infection leads to the selective destruction of neoplastic cells, mediated by functional viral replication. A positive correlation was identified between viral RNA accumulation and tumor cell death, with no replication observed in non-malignant cells. This study highlights the critical roles of cathepsins B, L, and S as mediators of the oncolytic process. The pharmacological inhibition of these enzymes significantly attenuated reovirus-induced cytotoxicity in melanoma and glioblastoma cells. Conversely, PKR production analysis revealed minimal activation in reovirus-infected tumor cells, suggesting that the hyperactivation of the RAS-signaling pathway and subsequent PKR inhibition do not directly contribute to the selective efficacy of reovirus. Moreover, infected tumor cells exhibited features of both apoptotic and non-apoptotic death, emphasizing the intricate mechanisms of reovirus-mediated oncolysis. These findings underscore the therapeutic promise of the Moscow strain of reovirus as a selective and potent oncolytic agent for targeting melanoma and glioblastoma cells.
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Affiliation(s)
- Yulia Ammour
- I.I. Mechnikov Research Institute for Vaccines and Sera, 105064 Moscow, Russia; (E.N.); (O.S.); (P.S.); (A.A.); (Y.Z.); (M.G.); (O.S.); (E.F.); (V.Z.)
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia;
| | - Eugenia Nikolaeva
- I.I. Mechnikov Research Institute for Vaccines and Sera, 105064 Moscow, Russia; (E.N.); (O.S.); (P.S.); (A.A.); (Y.Z.); (M.G.); (O.S.); (E.F.); (V.Z.)
| | - Olesya Sagimbaeva
- I.I. Mechnikov Research Institute for Vaccines and Sera, 105064 Moscow, Russia; (E.N.); (O.S.); (P.S.); (A.A.); (Y.Z.); (M.G.); (O.S.); (E.F.); (V.Z.)
| | - Pavel Shamsutdinov
- I.I. Mechnikov Research Institute for Vaccines and Sera, 105064 Moscow, Russia; (E.N.); (O.S.); (P.S.); (A.A.); (Y.Z.); (M.G.); (O.S.); (E.F.); (V.Z.)
| | - Anastasia Astapenko
- I.I. Mechnikov Research Institute for Vaccines and Sera, 105064 Moscow, Russia; (E.N.); (O.S.); (P.S.); (A.A.); (Y.Z.); (M.G.); (O.S.); (E.F.); (V.Z.)
| | - Yulia Zhelaeva
- I.I. Mechnikov Research Institute for Vaccines and Sera, 105064 Moscow, Russia; (E.N.); (O.S.); (P.S.); (A.A.); (Y.Z.); (M.G.); (O.S.); (E.F.); (V.Z.)
| | - Marina Gavrilova
- I.I. Mechnikov Research Institute for Vaccines and Sera, 105064 Moscow, Russia; (E.N.); (O.S.); (P.S.); (A.A.); (Y.Z.); (M.G.); (O.S.); (E.F.); (V.Z.)
| | - Olga Susova
- N.N. Blokhin Russian Cancer Research Center of the Ministry of Health of the Russian Federation, 115478 Moscow, Russia; (O.S.); (A.M.); (A.B.)
| | - Aleksey Mitrofanov
- N.N. Blokhin Russian Cancer Research Center of the Ministry of Health of the Russian Federation, 115478 Moscow, Russia; (O.S.); (A.M.); (A.B.)
| | - Ali Bekyashev
- N.N. Blokhin Russian Cancer Research Center of the Ministry of Health of the Russian Federation, 115478 Moscow, Russia; (O.S.); (A.M.); (A.B.)
| | - Tatiana Nasedkina
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia;
| | - Oxana Svitich
- I.I. Mechnikov Research Institute for Vaccines and Sera, 105064 Moscow, Russia; (E.N.); (O.S.); (P.S.); (A.A.); (Y.Z.); (M.G.); (O.S.); (E.F.); (V.Z.)
- I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation, 119146 Moscow, Russia
| | - Evgeny Faizuloev
- I.I. Mechnikov Research Institute for Vaccines and Sera, 105064 Moscow, Russia; (E.N.); (O.S.); (P.S.); (A.A.); (Y.Z.); (M.G.); (O.S.); (E.F.); (V.Z.)
| | - Vitaly Zverev
- I.I. Mechnikov Research Institute for Vaccines and Sera, 105064 Moscow, Russia; (E.N.); (O.S.); (P.S.); (A.A.); (Y.Z.); (M.G.); (O.S.); (E.F.); (V.Z.)
- I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation, 119146 Moscow, Russia
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8
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Wu S, Tu Q, Yuan H, Wu Z, Yang Y, Chen C, Huang C. Comprehensive Analysis for Predicting Prognoses and Immune Responses of m6A-Related lncRNAs in Women with Lung Adenocarcinoma. Biochem Genet 2024; 62:2702-2720. [PMID: 37999876 DOI: 10.1007/s10528-023-10572-w] [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: 06/18/2023] [Accepted: 10/26/2023] [Indexed: 11/25/2023]
Abstract
During the past decade, the average 5-year survival rate of patients with Lung adenocarcinoma (LUAD) has remained < 20%, although the targeted therapies and novel immunotherapy approaches have held promise. Epigenetic modifications could provide prognostic value as molecular biomarkers, and we aimed to identify the independent risk of m6A-related lncRNAs to establish a risk model for the clinical prediction of prognoses in women with LUAD. In this study, we first assessed 31 N6-methyladenosine (m6A)-related lncRNAs associated with overall survival. Moreover, we evaluated the expression of the oncogenic driver and the tumor immune microenvironment (TIME) in two female LUAD subtypes (clusters 1 and 2) using consensus clustering. We also found 16 m6A-related lncRNAs as the independent prognostic indicator of women with LUAD and established a risk model developed from these lncRNAs. We comprehensively investigated the correlation between the TIME and m6A-related lncRNA and found that m6A-related lncRNA may significantly affect the immune cell infiltration level in LUAD. In conclusion, our study provides evidence on the prognostic prediction in women with LUAD and may help elucidate the processes and mechanisms of m6A-regulated lncRNAs.
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Affiliation(s)
- Sijie Wu
- Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, #139 Renmin Road, Changsha, 410011, Hunan, China
| | - Qinxian Tu
- Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, #139 Renmin Road, Changsha, 410011, Hunan, China
| | - Haoyong Yuan
- Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, #139 Renmin Road, Changsha, 410011, Hunan, China
- Engineering Laboratory of Hunan Province for Cardiovascular Biomaterials, Changsha, 410008, Hunan, China
| | - Zhongshi Wu
- Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, #139 Renmin Road, Changsha, 410011, Hunan, China
- Engineering Laboratory of Hunan Province for Cardiovascular Biomaterials, Changsha, 410008, Hunan, China
| | - Yifeng Yang
- Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, #139 Renmin Road, Changsha, 410011, Hunan, China
| | - Chunyang Chen
- Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, #139 Renmin Road, Changsha, 410011, Hunan, China
- Engineering Laboratory of Hunan Province for Cardiovascular Biomaterials, Changsha, 410008, Hunan, China
| | - Can Huang
- Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, #139 Renmin Road, Changsha, 410011, Hunan, China.
- Engineering Laboratory of Hunan Province for Cardiovascular Biomaterials, Changsha, 410008, Hunan, China.
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9
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Nishibe N, Maruta S. Photocontrol of small GTPase Ras fused with a photoresponsive protein. J Biochem 2024; 176:11-21. [PMID: 38366640 DOI: 10.1093/jb/mvae017] [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: 10/26/2023] [Revised: 01/08/2024] [Accepted: 01/31/2024] [Indexed: 02/18/2024] Open
Abstract
The small GTPase Ras plays an important role in intracellular signal transduction and functions as a molecular switch. In this study, we used a photoresponsive protein as the molecular regulatory device to photoregulate Ras GTPase activity. Photo zipper (PZ), a variant of the photoresponsive protein Aureochrome1 developed by Hisatomi et al. was incorporated into the C-terminus of Ras as a fusion protein. The three constructs of the Ras-PZ fusion protein had spacers of different lengths between Ras and PZ. They were designed using an Escherichia coli expression system. The Ras-PZ fusion proteins exhibited photoisomerization upon blue light irradiation and in the dark. Ras-PZ dimerized upon light irradiation. Moreover, Ras GTPase activity, which is accelerated by the Ras regulators guanine nucleotide exchange factors and GTPase-activating proteins, is controlled by photoisomerization. It has been suggested that light-responsive proteins are applicable to the photoswitching of the enzymatic activity of small GTPases as photoregulatory molecular devices.
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Affiliation(s)
- Nobuyuki Nishibe
- Department of Biosciences, Graduate School of Science and Engineering Soka University, 1-236 Tangi-cho, Hachioji, Tokyo 192-8577, Japan
| | - Shinsaku Maruta
- Department of Biosciences, Graduate School of Science and Engineering Soka University, 1-236 Tangi-cho, Hachioji, Tokyo 192-8577, Japan
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10
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Lee AA, Kim NH, Alvarez S, Ren H, DeGrandchamp JB, Lew LJN, Groves JT. Bimodality in Ras signaling originates from processivity of the Ras activator SOS without deterministic bistability. SCIENCE ADVANCES 2024; 10:eadi0707. [PMID: 38905351 PMCID: PMC11192083 DOI: 10.1126/sciadv.adi0707] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Accepted: 05/15/2024] [Indexed: 06/23/2024]
Abstract
Ras is a small GTPase that is central to important functional decisions in diverse cell types. An important aspect of Ras signaling is its ability to exhibit bimodal or switch-like activity. We describe the total reconstitution of a receptor-mediated Ras activation-deactivation reaction catalyzed by SOS and p120-RasGAP on supported lipid membrane microarrays. The results reveal a bimodal Ras activation response, which is not a result of deterministic bistability but is rather driven by the distinct processivity of the Ras activator, SOS. Furthermore, the bimodal response is controlled by the condensation state of the scaffold protein, LAT, to which SOS is recruited. Processivity-driven bimodality leads to stochastic bursts of Ras activation even under strongly deactivating conditions. This behavior contrasts deterministic bistability and may be more resistant to pharmacological inhibition.
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Affiliation(s)
- Albert A. Lee
- Department of Chemistry, University of California, Berkeley, CA 94720, USA
- Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA
| | - Neil H. Kim
- Department of Chemistry, University of California, Berkeley, CA 94720, USA
| | - Steven Alvarez
- Department of Chemistry, University of California, Berkeley, CA 94720, USA
- Department of Materials Science and Engineering, University of California, Berkeley, CA 94720, USA
| | - He Ren
- Department of Chemistry, University of California, Berkeley, CA 94720, USA
| | | | - L. J. Nugent Lew
- Department of Chemistry, University of California, Berkeley, CA 94720, USA
| | - Jay T. Groves
- Department of Chemistry, University of California, Berkeley, CA 94720, USA
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11
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Vazaios K, Stavrakaki Ε, Vogelezang LB, Ju J, Waranecki P, Metselaar DS, Meel MH, Kemp V, van den Hoogen BG, Hoeben RC, Chiocca EA, Goins WF, Stubbs A, Li Y, Alonso MM, Calkoen FG, Hulleman E, van der Lugt J, Lamfers ML. The heterogeneous sensitivity of pediatric brain tumors to different oncolytic viruses is predicted by unique gene expression profiles. MOLECULAR THERAPY. ONCOLOGY 2024; 32:200804. [PMID: 38694569 PMCID: PMC11060958 DOI: 10.1016/j.omton.2024.200804] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Accepted: 04/11/2024] [Indexed: 05/04/2024]
Abstract
Despite decades of research, the prognosis of high-grade pediatric brain tumors (PBTs) remains dismal; however, recent cases of favorable clinical responses were documented in clinical trials using oncolytic viruses (OVs). In the current study, we employed four different species of OVs: adenovirus Delta24-RGD, herpes simplex virus rQNestin34.5v1, reovirus R124, and the non-virulent Newcastle disease virus rNDV-F0-GFP against three entities of PBTs (high-grade gliomas, atypical teratoid/rhabdoid tumors, and ependymomas) to determine their in vitro efficacy. These four OVs were screened on 14 patient-derived PBT cell cultures and the degree of oncolysis was assessed using an ATP-based assay. Subsequently, the observed viral efficacies were correlated to whole transcriptome data and Gene Ontology analysis was performed. Although no significant tumor type-specific OV efficacy was observed, the analysis revealed the intrinsic biological processes that associated with OV efficacy. The predictive power of the identified expression profiles was further validated in vitro by screening additional PBTs. In summary, our results demonstrate OV susceptibility of multiple patient-derived PBT entities and the ability to predict in vitro responses to OVs using unique expression profiles. Such profiles may hold promise for future OV preselection with effective oncolytic potency in a specific tumor, therewith potentially improving OV responses.
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Affiliation(s)
- Konstantinos Vazaios
- Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, the Netherlands
- Department of Neurosurgery, Brain Tumor Center, Erasmus Medical Center, Dr. Molewaterplein 40, 3015 GD Rotterdam, the Netherlands
- Center for Translational Immunology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands
| | - Εftychia Stavrakaki
- Department of Neurosurgery, Brain Tumor Center, Erasmus Medical Center, Dr. Molewaterplein 40, 3015 GD Rotterdam, the Netherlands
| | - Lisette B. Vogelezang
- Department of Neurosurgery, Brain Tumor Center, Erasmus Medical Center, Dr. Molewaterplein 40, 3015 GD Rotterdam, the Netherlands
| | - Jie Ju
- Department of Pathology and Clinical Bioinformatics, Erasmus Medical Center, Dr. Molewaterplein 40, 3015 GD Rotterdam, the Netherlands
| | - Piotr Waranecki
- Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, the Netherlands
| | - Dennis S. Metselaar
- Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, the Netherlands
| | - Michaël H. Meel
- Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, the Netherlands
- Department of Pediatrics, Wilhelmina Children’s Hospital, University Medical Center Utrecht, Lundlaan 6, 3584 EA Utrecht, the Netherlands
| | - Vera Kemp
- Department of Cell and Chemical Biology, Leiden University Medical Center, Einthovenweg 20, 2333 ZC Leiden, the Netherlands
| | | | - Rob C. Hoeben
- Department of Cell and Chemical Biology, Leiden University Medical Center, Einthovenweg 20, 2333 ZC Leiden, the Netherlands
| | - E. Antonio Chiocca
- Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA
| | - William F. Goins
- Department of Microbiology & Molecular Genetics, University of Pittsburgh School of Medicine, 450 Technology Dr, Pittsburgh, PA 15219, USA
| | - Andrew Stubbs
- Department of Pathology and Clinical Bioinformatics, Erasmus Medical Center, Dr. Molewaterplein 40, 3015 GD Rotterdam, the Netherlands
| | - Yunlei Li
- Department of Pathology and Clinical Bioinformatics, Erasmus Medical Center, Dr. Molewaterplein 40, 3015 GD Rotterdam, the Netherlands
| | - Marta M. Alonso
- Program in Solid Tumors, Center for Applied Medical Research (CIMA), Avda. de Pío XII, 55, 31008 Pamplona, Spain
- Department of Pediatrics, Clínica Universidad de Navarra, Av. de Pío XII, 36, 31008 Pamplona, Spain
- Health Research Institute of Navarra (IDISNA), Av. de Pío XII, 36, 31008 Pamplona, Spain
| | - Friso G. Calkoen
- Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, the Netherlands
| | - Esther Hulleman
- Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, the Netherlands
| | - Jasper van der Lugt
- Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, the Netherlands
| | - Martine L.M. Lamfers
- Department of Neurosurgery, Brain Tumor Center, Erasmus Medical Center, Dr. Molewaterplein 40, 3015 GD Rotterdam, the Netherlands
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12
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Costa ISD, Junot T, Silva FL, Felix W, Cardozo Fh JL, Pereira de Araujo AF, Pais do Amaral C, Gonçalves S, Santos NC, Leite JRSA, Bloch C, Brand GD. Occurrence and evolutionary conservation analysis of α-helical cationic amphiphilic segments in the human proteome. FEBS J 2024; 291:547-565. [PMID: 37945538 DOI: 10.1111/febs.16997] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 09/14/2023] [Accepted: 10/20/2023] [Indexed: 11/12/2023]
Abstract
The existence of encrypted fragments with antimicrobial activity in human proteins has been thoroughly demonstrated in the literature. Recently, algorithms for the large-scale identification of these segments in whole proteomes were developed, and the pervasiveness of this phenomenon was stated. These algorithms typically mine encrypted cationic and amphiphilic segments of proteins, which, when synthesized as individual polypeptide sequences, exert antimicrobial activity by membrane disruption. In the present report, the human reference proteome was submitted to the software kamal for the uncovering of protein segments that correspond to putative intragenic antimicrobial peptides (IAPs). The assessment of the identity of these segments, frequency, functional classes of parent proteins, structural relevance, and evolutionary conservation of amino acid residues within their corresponding proteins was conducted in silico. Additionally, the antimicrobial and anticancer activity of six selected synthetic peptides was evaluated. Our results indicate that cationic and amphiphilic segments can be found in 2% of all human proteins, but are more common in transmembrane and peripheral membrane proteins. These segments are surface-exposed basic patches whose amino acid residues present similar conservation scores to other residues with similar solvent accessibility. Moreover, the antimicrobial and anticancer activity of the synthetic putative IAP sequences was irrespective to whether these are associated to membranes in the cellular setting. Our study discusses these findings in light of the current understanding of encrypted peptide sequences, offering some insights into the relevance of these segments to the organism in the context of their harboring proteins or as separate polypeptide sequences.
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Affiliation(s)
- Igor S D Costa
- Laboratório de Síntese e Análise de Biomoléculas - LSAB, Instituto de Química, Universidade de Brasília, Brazil
| | - Tiago Junot
- Laboratório de Síntese e Análise de Biomoléculas - LSAB, Instituto de Química, Universidade de Brasília, Brazil
| | - Fernanda L Silva
- Laboratório de Síntese e Análise de Biomoléculas - LSAB, Instituto de Química, Universidade de Brasília, Brazil
| | - Wanessa Felix
- Núcleo de Pesquisa em Morfologia e Imunologia Aplicada - NuPMIA, Faculdade de Medicina, Universidade de Brasília, Brazil
| | - José L Cardozo Fh
- Laboratório de Espectrometria de Massa - LEM, Embrapa Recursos Genéticos e Biotecnologia, Brasília, Brazil
| | - Antonio F Pereira de Araujo
- Laboratório de Biofísica Teórica e Computacional, Departamento de Biologia Celular, Universidade de Brasília, Brazil
| | | | - Sónia Gonçalves
- Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Portugal
| | - Nuno C Santos
- Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Portugal
| | - José R S A Leite
- Núcleo de Pesquisa em Morfologia e Imunologia Aplicada - NuPMIA, Faculdade de Medicina, Universidade de Brasília, Brazil
| | - Carlos Bloch
- Laboratório de Espectrometria de Massa - LEM, Embrapa Recursos Genéticos e Biotecnologia, Brasília, Brazil
| | - Guilherme D Brand
- Laboratório de Síntese e Análise de Biomoléculas - LSAB, Instituto de Química, Universidade de Brasília, Brazil
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13
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Xu Y, Du W, Xiao Y, Gao K, Li J, Li S. A Number of the N-terminal RASSF Family: RASSF7. Anticancer Agents Med Chem 2024; 24:889-895. [PMID: 36200241 DOI: 10.2174/1871520622666220930094149] [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: 04/21/2022] [Revised: 07/25/2022] [Accepted: 09/05/2022] [Indexed: 11/22/2022]
Abstract
The Ras association domain family 7 (RASSF7, also named HRC1), a potential tumor-related gene, located on human chromosome 11p15, has been identified as an important member of the N-terminal RASSF family. Whereas, the molecular biological mechanisms of RASSF7 in tumorigenesis remain to be further established. We perform a systematic review of the literature and assessment from PUBMED and MEDLINE databases in this article. RASSF7 plays a significant role in mitosis, microtubule growth, apoptosis, proliferation and differentiation. Many research literature shows that the RASSF7 could promote the occurrence and advance of human tumors by regulating Aurora B, MKK4, MKK7, JNK, YAP, MEK, and ERK, whereas, it might inhibit c-Myc and thus lead to the suppression of tumorigenesis. The pregulation of RASSF7 often occurs in various malignancies such as lung cancer, neuroblastoma, thyroid neoplasm, hepatocellular cancer, breast cancer and gastric cancer. The expression stage of RASSF7 is positively correlated with the tumor TNM stage. In this review, we primarily elaborate on the acknowledged structure and progress in the various biomechanisms and research advances of RASSF7, especially the potential relevant signaling pathways. We hope that RASSF7 , a prospective therapeutic target for human malignancies, could play an available role in future anti-cancer treatment.
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Affiliation(s)
- Yang Xu
- Department of Urology, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, People's Republic of China
- Department of Urology, Huzhou Central Hospital, Huzhou, Zhejiang, 313000, People's Republic of China
| | - Wei Du
- Department of Urology, Wanbei Coal-Electricity Group General Hospital, Suzhou 234000, People's Republic of China
| | - Yongshuang Xiao
- Department of Urology, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, People's Republic of China
| | - Keyu Gao
- Department of Urology, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, People's Republic of China
| | - Jie Li
- Department of Urology, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, People's Republic of China
| | - Shuofeng Li
- Department of Urology, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, People's Republic of China
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14
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Jurado M, Zorzano A, Castaño O. Cooperativity and oscillations: Regulatory mechanisms of K-Ras nanoclusters. Comput Biol Med 2023; 166:107455. [PMID: 37742420 DOI: 10.1016/j.compbiomed.2023.107455] [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: 11/28/2022] [Revised: 08/07/2023] [Accepted: 09/04/2023] [Indexed: 09/26/2023]
Abstract
K-Ras nanoclusters (NCs) concentrate all required molecules belonging to the extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) pathway in a small area where signaling events take place, increasing efficiency and specificity of signaling. Such nanostructures are characterized by controlled sizes and lifetimes distributions, but there is a poor understanding of the mechanisms involved in their dynamics of growth/decay. Here, a minimum computational model is presented to analyze the behavior of K-Ras NCs as cooperative dynamic structures that self-regulate their growth and decay according to their size. Indeed, the proposed model reveals that the growth and the local production of a K-Ras nanocluster depend positively on its actual size, whilst its lifetime is inversely proportional to the root of its size. The cooperative binding between the structural constituents of the NC (K-Ras proteins) induces oscillations in the size distributions of K-Ras NCs allowing them to range within controlled values, regulating the growth/decay dynamics of these NCs. Thereby, the size of a K-Ras NC is proposed as a key factor to regulate cell signaling, opening a range of possibilities to develop strategies for use in chronic diseases and cancer.
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Affiliation(s)
- Manuel Jurado
- Faculty of Pharmacy, University of Barcelona, Barcelona, Spain
| | - Antonio Zorzano
- Institute for Research in Biomedicine (IRB), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain; CIBER of Diabetes and Associated Metabolic Diseases, Barcelona, Spain; Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, University of Barcelona, Barcelona, Spain.
| | - Oscar Castaño
- Electronics and Biomedical Engineering, Universitat de Barcelona (UB), Barcelona, Spain; Nanobioengineering and Biomaterials, Institute of Nanoscience and Nanotechnology of the University of Barcelona, Barcelona, Spain
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15
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Simão S, Agostinho RR, Martínez-Ruiz A, Araújo IM. Regulation of Ras Signaling by S-Nitrosylation. Antioxidants (Basel) 2023; 12:1562. [PMID: 37627556 PMCID: PMC10451275 DOI: 10.3390/antiox12081562] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 07/28/2023] [Accepted: 08/02/2023] [Indexed: 08/27/2023] Open
Abstract
Ras are a family of small GTPases that function as signal transduction mediators and are involved in cell proliferation, migration, differentiation and survival. The significance of Ras is further evidenced by the fact that Ras genes are among the most mutated oncogenes in different types of cancers. After translation, Ras proteins can be targets of post-translational modifications (PTM), which can alter the intracellular dynamics of the protein. In this review, we will focus on how S-nitrosylation of Ras affects the way these proteins interact with membranes, its cellular localization, and its activity. S-Nitrosylation occurs when a nitrosyl moiety of nitric oxide (NO) is covalently attached to a thiol group of a cysteine residue in a target protein. In Ras, the conserved Cys118 is the most surface-exposed Cys and the preferable residue for NO action, leading to the initiation of transduction events. Ras transduces the mitogen-activated protein kinases (MAPK), the phosphoinositide-3 kinase (PI3K) and the RalGEF cellular pathways. S-Nitrosylation of elements of the RalGEF cascade remains to be identified. On the contrary, it is well established that several components of the MAPK and PI3K pathways, as well as different proteins associated with these cascades, can be modified by S-nitrosylation. Overall, this review presents a better understanding of Ras S-nitrosylation, increasing the knowledge on the dynamics of these proteins in the presence of NO and the underlying implications in cellular signaling.
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Affiliation(s)
- Sónia Simão
- Algarve Biomedical Center Research Institute (ABC-RI), University of Algarve, 8005-139 Faro, Portugal;
- Faculty of Medicine and Biomedical Sciences, University of Algarve, 8005-139 Faro, Portugal
| | - Rafaela Ribeiro Agostinho
- Algarve Biomedical Center Research Institute (ABC-RI), University of Algarve, 8005-139 Faro, Portugal;
- Faculty of Medicine and Biomedical Sciences, University of Algarve, 8005-139 Faro, Portugal
| | - Antonio Martínez-Ruiz
- Unidad de Investigación, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria Princesa, 28009 Madrid, Spain;
- Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad Complutense de Madrid, 28040 Madrid, Spain
| | - Inês Maria Araújo
- Algarve Biomedical Center Research Institute (ABC-RI), University of Algarve, 8005-139 Faro, Portugal;
- Faculty of Medicine and Biomedical Sciences, University of Algarve, 8005-139 Faro, Portugal
- Champalimaud Research Program, 1400-038 Lisbon, Portugal
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16
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Lee AA, Kim NH, Alvarez S, Ren H, DeGrandchamp JB, Lew LJN, Groves JT. Bimodality in Ras signaling originates from processivity of the Ras activator SOS without classic kinetic bistability. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.07.17.549263. [PMID: 37503094 PMCID: PMC10370109 DOI: 10.1101/2023.07.17.549263] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/29/2023]
Abstract
Ras is a small GTPase that is central to important functional decisions in diverse cell types. An important aspect of Ras signaling is its ability to exhibit bimodal, or switch-like activity. We describe the total reconstitution of a receptor-mediated Ras activation-deactivation reaction catalyzed by SOS and p120-RasGAP on supported lipid membrane microarrays. The results reveal a bimodal Ras activation response, which is not a result of classic kinetic bistability, but is rather driven by the distinct processivity of the Ras activator, SOS. Furthermore, the bimodal response is controlled by the condensation state of the scaffold protein, LAT, to which SOS is recruited. Processivity-driven bimodality leads to stochastic bursts of Ras activation even under strongly deactivating conditions. This behavior contrasts classic kinetic bistability and is distinctly more resistant to pharmacological inhibition.
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17
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Omar FA, Brown TC, Gillanders WE, Fleming TP, Smith MA, Bremner RM, Sankpal NV. Cytosolic EpCAM cooperates with H-Ras to regulate epithelial to mesenchymal transition through ZEB1. PLoS One 2023; 18:e0285707. [PMID: 37192201 PMCID: PMC10187930 DOI: 10.1371/journal.pone.0285707] [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] [Received: 12/20/2022] [Accepted: 04/30/2023] [Indexed: 05/18/2023] Open
Abstract
Next generation sequencing of human cancer mutations has identified novel therapeutic targets. Activating Ras oncogene mutations play a central role in oncogenesis, and Ras-driven tumorigenesis upregulates an array of genes and signaling cascades that can transform normal cells into tumor cells. In this study, we investigated the role of altered localization of epithelial cell adhesion molecule (EpCAM) in Ras-expressing cells. Analysis of microarray data demonstrated that Ras expression induced EpCAM expression in normal breast epithelial cells. Fluorescent and confocal microscopy showed that H-Ras mediated transformation also promoted epithelial-to-mesenchymal transition (EMT) together with EpCAM. To consistently localize EpCAM in the cytosol, we generated a cancer-associated EpCAM mutant (EpCAM-L240A) that is retained in the cytosol compartment. Normal MCF-10A cells were transduced with H-Ras together with EpCAM wild-type (WT) or EpCAM-L240A. WT-EpCAM marginally effected invasion, proliferation, and soft agar growth. EpCAM-L240A, however, markedly altered cells and transformed to mesenchymal phenotype. Ras-EpCAM-L240A expression also promoted expression of EMT factors FRA1, ZEB1 with inflammatory cytokines IL-6, IL-8, and IL1. This altered morphology was reversed using MEK-specific inhibitors and to some extent JNK inhibition. Furthermore, these transformed cells were sensitized to apoptosis using paclitaxel and quercetin, but not other therapies. For the first time, we have demonstrated that EpCAM mutations can cooperate with H-Ras and promote EMT. Collectively, our results highlight future therapeutic opportunities in EpCAM and Ras mutated cancers.
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Affiliation(s)
- Fatma A. Omar
- Norton Thoracic Institute, St. Joseph’s Hospital and Medical Center, Phoenix, Arizona, United States of America
| | - Taylor C. Brown
- Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri, United States of America
| | - William E. Gillanders
- Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri, United States of America
| | - Timothy P. Fleming
- Norton Thoracic Institute, St. Joseph’s Hospital and Medical Center, Phoenix, Arizona, United States of America
| | - Michael A. Smith
- Norton Thoracic Institute, St. Joseph’s Hospital and Medical Center, Phoenix, Arizona, United States of America
| | - Ross M. Bremner
- Norton Thoracic Institute, St. Joseph’s Hospital and Medical Center, Phoenix, Arizona, United States of America
| | - Narendra V. Sankpal
- Norton Thoracic Institute, St. Joseph’s Hospital and Medical Center, Phoenix, Arizona, United States of America
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18
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Solomon PE, Kirkemo LL, Wilson GM, Leung KK, Almond MH, Sayles LC, Sweet-Cordero EA, Rosenberg OS, Coon JJ, Wells JA. Discovery Proteomics Analysis Determines That Driver Oncogenes Suppress Antiviral Defense Pathways Through Reduction in Interferon-β Autocrine Stimulation. Mol Cell Proteomics 2022; 21:100247. [PMID: 35594991 PMCID: PMC9212846 DOI: 10.1016/j.mcpro.2022.100247] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Revised: 04/27/2022] [Accepted: 05/12/2022] [Indexed: 11/25/2022] Open
Abstract
Since the discovery of oncogenes, there has been tremendous interest to understand their mechanistic basis and to develop broadly actionable therapeutics. Some of the most frequently activated oncogenes driving diverse cancers are c-MYC, EGFR, HER2, AKT, KRAS, BRAF, and MEK. Using a reductionist approach, we explored how cellular proteomes are remodeled in isogenic cell lines engineered with or without these driver oncogenes. The most striking discovery for all oncogenic models was the systematic downregulation of scores of antiviral proteins regulated by type 1 interferon. These findings extended to cancer cell lines and patient-derived xenograft models of highly refractory pancreatic cancer and osteosarcoma driven by KRAS and MYC oncogenes. The oncogenes reduced basal expression of and autocrine stimulation by type 1 interferon causing remarkable convergence on common phenotypic and functional profiles. In particular, there was dramatically lower expression of dsRNA sensors including DDX58 (RIG-I) and OAS proteins, which resulted in attenuated functional responses when the oncogenic cells were treated with the dsRNA mimetic, polyI:C, and increased susceptibility to infection with an RNA virus shown using SARS-CoV-2. Our reductionist approach provides molecular and functional insights connected to immune evasion hallmarks in cancers and suggests therapeutic opportunities.
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Affiliation(s)
- Paige E Solomon
- Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California, USA
| | - Lisa L Kirkemo
- Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California, USA
| | - Gary M Wilson
- Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin, USA; Department of Biomolecular Chemistry, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Kevin K Leung
- Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California, USA
| | - Mark H Almond
- Division of Infectious Diseases, Department of Medicine, UCSF Medical Center, University of California, San Francisco, California, USA
| | - Leanne C Sayles
- Department of Pediatrics, University of California San Francisco, California, USA
| | | | - Oren S Rosenberg
- Division of Infectious Diseases, Department of Medicine, UCSF Medical Center, University of California, San Francisco, California, USA; Department of Biophysics and Biochemistry, Chan Zuckerberg Biohub, San Francisco, California, USA
| | - Joshua J Coon
- Department of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin, USA; Department of Biomolecular Chemistry, University of Wisconsin-Madison, Madison, Wisconsin, USA; National Center for Quantitative Biology of Complex Systems, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - James A Wells
- Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California, USA; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, California, USA.
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19
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Aloperine: A Potent Modulator of Crucial Biological Mechanisms in Multiple Diseases. Biomedicines 2022; 10:biomedicines10040905. [PMID: 35453655 PMCID: PMC9028564 DOI: 10.3390/biomedicines10040905] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Revised: 03/30/2022] [Accepted: 03/31/2022] [Indexed: 01/18/2023] Open
Abstract
Aloperine is an alkaloid found in the seeds and leaves of the medicinal plant Sophora alopecuroides L. It has been used as herbal medicine in China for centuries due to its potent anti-inflammatory, antioxidant, antibacterial, and antiviral properties. Recently, aloperine has been widely investigated for its therapeutic activities. Aloperine is proven to be an effective therapeutic agent against many human pathological conditions, including cancer, viral diseases, and cardiovascular and inflammatory disorders. Aloperine is reported to exert therapeutic effects through triggering various biological processes, including cell cycle arrest, apoptosis, autophagy, suppressing cell migration, and invasion. It has also been found to be associated with the modulation of various signaling pathways in different diseases. In this review, we summarize the most recent knowledge on the modulatory effects of aloperine on various critical biological processes and signaling mechanisms, including the PI3K, Akt, NF-κB, Ras, and Nrf2 pathways. These data demonstrate that aloperine is a promising therapeutic candidate. Being a potent modulator of signaling mechanisms, aloperine can be employed in clinical settings to treat various human disorders in the future.
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20
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Genetic Background of Polycythemia Vera. Genes (Basel) 2022; 13:genes13040637. [PMID: 35456443 PMCID: PMC9027017 DOI: 10.3390/genes13040637] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 03/25/2022] [Accepted: 03/26/2022] [Indexed: 02/06/2023] Open
Abstract
Polycythemia vera belongs to myeloproliferative neoplasms, essentially by affecting the erythroblastic lineage. JAK2 alterations have emerged as major driver mutations triggering PV-phenotype with the V617F mutation detected in nearly 98% of cases. That’s why JAK2 targeting therapeutic strategies have rapidly emerged to counter the aggravation of the disease. Over decades of research, to go further in the understanding of the disease and its evolution, a wide panel of genetic alterations affecting multiple genes has been highlighted. These are mainly involved in alternative splicing, epigenetic, miRNA regulation, intracellular signaling, and transcription factors expression. If JAK2 mutation, irrespective of the nature of the alteration, is known to be a crucial event for the disease to initiate, additional mutations seem to be markers of progression and poor prognosis. These discoveries have helped to characterize the complex genomic landscape of PV, resulting in potentially new adapted therapeutic strategies for patients concerning all the genetic interferences.
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21
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Abstract
Activating mutations in RAS genes are the most common genetic driver of human cancers. Yet, drugging this small GTPase has proven extremely challenging and therapeutic strategies targeting these recurrent alterations have long had limited success. To circumvent this difficulty, research has focused on the molecular dissection of the RAS pathway to gain a more-precise mechanistic understanding of its regulation, with the hope to identify new pharmacological approaches. Here, we review the current knowledge on the (dys)regulation of the RAS pathway, using melanoma as a paradigm. We first present a map of the main proteins involved in the RAS pathway, highlighting recent insights into their molecular roles and diverse mechanisms of regulation. We then overview genetic data pertaining to RAS pathway alterations in melanoma, along with insight into other cancers, that inform the biological function of members of the pathway. Finally, we describe the clinical implications of RAS pathway dysregulation in melanoma, discuss past and current approaches aimed at drugging the RAS pathway, and outline future opportunities for therapeutic development. Summary: This Review describes the molecular regulation of the RAS pathway, presents the clinical consequences of its pathological activation in human cancer, and highlights recent advances towards its therapeutic inhibition, using melanoma as an example.
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Affiliation(s)
- Amira Al Mahi
- Centre de Recherche en Cancérologie de Lyon, Centre Léon Bérard, INSERM U1052 CNRS UMR5286, Tumor Escape, Resistance and Immunity Department, 69008 Lyon, France
| | - Julien Ablain
- Centre de Recherche en Cancérologie de Lyon, Centre Léon Bérard, INSERM U1052 CNRS UMR5286, Tumor Escape, Resistance and Immunity Department, 69008 Lyon, France
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22
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Kolawole OR, Kashfi K. NSAIDs and Cancer Resolution: New Paradigms beyond Cyclooxygenase. Int J Mol Sci 2022; 23:1432. [PMID: 35163356 PMCID: PMC8836048 DOI: 10.3390/ijms23031432] [Citation(s) in RCA: 55] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 01/19/2022] [Accepted: 01/20/2022] [Indexed: 12/12/2022] Open
Abstract
Acute inflammation or resolved inflammation is an adaptive host defense mechanism and is self-limiting, which returns the body to a state of homeostasis. However, unresolved, uncontrolled, or chronic inflammation may lead to various maladies, including cancer. Important evidence that links inflammation and cancer is that nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, reduce the risk and mortality from many cancers. The fact that NSAIDs inhibit the eicosanoid pathway prompted mechanistic drug developmental work focusing on cyclooxygenase (COX) and its products. The increased prostaglandin E2 levels and the overexpression of COX-2 in the colon and many other cancers provided the rationale for clinical trials with COX-2 inhibitors for cancer prevention or treatment. However, NSAIDs do not require the presence of COX-2 to prevent cancer. In this review, we highlight the effects of NSAIDs and selective COX-2 inhibitors (COXIBs) on targets beyond COX-2 that have shown to be important against many cancers. Finally, we hone in on specialized pro-resolving mediators (SPMs) that are biosynthesized locally and, in a time, -dependent manner to promote the resolution of inflammation and subsequent tissue healing. Different classes of SPMs are reviewed, highlighting aspirin's potential in triggering the production of these resolution-promoting mediators (resolvins, lipoxins, protectins, and maresins), which show promise in inhibiting cancer growth and metastasis.
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Affiliation(s)
- Oluwafunke R. Kolawole
- Department of Molecular, Cellular and Biomedical Sciences, Sophie Davis School of Biomedical Education, City University of New York School of Medicine, New York, NY 10031, USA;
| | - Khosrow Kashfi
- Department of Molecular, Cellular and Biomedical Sciences, Sophie Davis School of Biomedical Education, City University of New York School of Medicine, New York, NY 10031, USA;
- Graduate Program in Biology, City University of New York Graduate Center, New York, NY 10091, USA
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23
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Blaquier JB, Cardona AF, Recondo G. Resistance to KRAS G12C Inhibitors in Non-Small Cell Lung Cancer. Front Oncol 2021; 11:787585. [PMID: 35004309 PMCID: PMC8739760 DOI: 10.3389/fonc.2021.787585] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 12/09/2021] [Indexed: 12/14/2022] Open
Abstract
KRAS mutations are one of the most prevalent oncogenic alterations in cancer. Until recently, drug development targeting KRAS did not convey clinical benefits to patients. Specific KRASG12C inhibitors, such as sotorasib and adagrasib, have been designed to bind to the protein's mutant structure and block KRASG12C in its GDP-bound inactive state. Phase 1/2 trials have shown promising anti-tumor activity, especially in pretreated non-small cell lung cancer patients. As expected, both primary and secondary resistance to KRASG12C inhibitors invariably occurs, and molecular mechanisms have been characterized in pre-clinical models and patients. Several mechanisms such as tyrosine kinase receptors (RTKs) mediated feedback reactivation of ERK-dependent signaling can result in intrinsic resistance to KRAS target therapy. Acquired resistance to KRASG12C inhibitors include novel KRAS mutations such as Y96D/C and other RAS-MAPK effector protein mutations. This review focuses on the intrinsic and acquired mechanisms of resistance to KRASG12C inhibitors in KRASG12C mutant non-small cell lung cancer and the potential clinical strategies to overcome or prevent it.
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Affiliation(s)
- Juan Bautista Blaquier
- Thoracic Oncology Unit, Medical Oncology, Center for Medical Education and Clinical Research (CEMIC), Buenos Aires, Argentina
| | - Andrés Felipe Cardona
- Luis Carlos Sarmiento Angulo Cancer Treatment and Research Center (CTIC), Bogotá, Colombia
- Foundation for Clinical and Applied Cancer Research (FICMAC), Bogotá, Colombia
- Molecular Oncology and Biology Systems Research Group (FOX-G/ONCOLGroup), Universidad El Bosque, Bogotá, Colombia
| | - Gonzalo Recondo
- Thoracic Oncology Unit, Medical Oncology, Center for Medical Education and Clinical Research (CEMIC), Buenos Aires, Argentina
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24
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Schmukler E, Pinkas-Kramarski R. The interplay between Ras, Autophagy and cancer. ADVANCES IN CANCER BIOLOGY - METASTASIS 2021; 3:100014. [DOI: 10.1016/j.adcanc.2021.100014] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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25
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Pre-Clinical and Clinical Applications of Small Interfering RNAs (siRNA) and Co-Delivery Systems for Pancreatic Cancer Therapy. Cells 2021; 10:cells10123348. [PMID: 34943856 PMCID: PMC8699513 DOI: 10.3390/cells10123348] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Accepted: 11/17/2021] [Indexed: 02/07/2023] Open
Abstract
Pancreatic cancer (PC) is one of the leading causes of death and is the fourth most malignant tumor in men. The epigenetic and genetic alterations appear to be responsible for development of PC. Small interfering RNA (siRNA) is a powerful genetic tool that can bind to its target and reduce expression level of a specific gene. The various critical genes involved in PC progression can be effectively targeted using diverse siRNAs. Moreover, siRNAs can enhance efficacy of chemotherapy and radiotherapy in inhibiting PC progression. However, siRNAs suffer from different off target effects and their degradation by enzymes in serum can diminish their potential in gene silencing. Loading siRNAs on nanoparticles can effectively protect them against degradation and can inhibit off target actions by facilitating targeted delivery. This can lead to enhanced efficacy of siRNAs in PC therapy. Moreover, different kinds of nanoparticles such as polymeric nanoparticles, lipid nanoparticles and metal nanostructures have been applied for optimal delivery of siRNAs that are discussed in this article. This review also reveals that how naked siRNAs and their delivery systems can be exploited in treatment of PC and as siRNAs are currently being applied in clinical trials, significant progress can be made by translating the current findings into the clinical settings.
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26
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Du Y, Luo S, Zhou X. Enterococcus faecium Regulates Honey Bee Developmental Genes. Int J Mol Sci 2021; 22:ijms222212105. [PMID: 34829986 PMCID: PMC8621553 DOI: 10.3390/ijms222212105] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2021] [Revised: 11/01/2021] [Accepted: 11/05/2021] [Indexed: 11/24/2022] Open
Abstract
Honey bees provide essential pollination services to the terrestrial ecosystem and produce important agricultural products. As a beneficial lactic acid bacterium, Enterococcus faecium is often supplied as a probiotic for honey bees and other animals. However, the underlying mechanisms of its actions and possible safety risks are not well understood. We present the first complete genome sequence of E. faecium isolated from the honey bee gut using nanopore sequencing, and investigate the effects and mechanisms of interactions between E. faecium and honey bees via transcriptome and miRNA analysis. E. faecium colonization increased honey bee gut weight. Transcriptome analysis showed that developmental genes were up-regulated. In accordance, the target genes of the down-regulated miRNAs were enriched in developmental pathways. We describe how E. faecium increases honey bee gut weight at the transcriptional and post-transcriptional levels, and add insights about how miRNAs mediate host and bacteria interactions.
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Affiliation(s)
- Yating Du
- College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China;
- Department of Entomology, College of Plant Protection, China Agricultural University, Beijing 100193, China
| | - Shiqi Luo
- Department of Entomology, College of Plant Protection, China Agricultural University, Beijing 100193, China
- Correspondence: (S.L.); (X.Z.)
| | - Xin Zhou
- Department of Entomology, College of Plant Protection, China Agricultural University, Beijing 100193, China
- Correspondence: (S.L.); (X.Z.)
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27
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Nahar R, Iwata S, Morita D, Tahara Y, Sugimoto Y, Miyata M, Maruta S. Multimerization of Small G-protein H-Ras Induced by Chemical Modification at Hyper Variable Region with Caged Compound. J Biochem 2021; 171:215-225. [PMID: 34738101 DOI: 10.1093/jb/mvab120] [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: 09/04/2021] [Accepted: 10/29/2021] [Indexed: 11/15/2022] Open
Abstract
The lipid-anchored small G protein Ras is a central regulator of cellular signal transduction processes, thereby functioning as a molecular switch. Ras forms a nanocluster on the plasma membrane by modifying lipids in the hypervariable region (HVR) at the C-terminus to exhibit physiological functions. In this study, we demonstrated that chemical modification of cysteine residues in HVR with caged compounds (instead of lipidation) induces multimerization of H-Ras. The sulfhydryl-reactive caged compound, 2-nitrobenzyl bromide (NBB), was stoichiometrically incorporated into the cysteine residue of HVR and induced the formation of the Ras multimer. Light irradiation induced the elimination of the 2-nitrobenzyl group, resulting in the conversion of the multimer to a monomer. SEC-HPLC and small-angle X-ray scattering (SAXS) analysis revealed that H-Ras forms a pentamer. Electron microscopic observation of the multimer showed a circular ring shape, which is consistent with the structure estimated from X-ray scattering. The shape of the multimer may reflect the physiological state of Ras. It was suggested that the multimerization and monomerization of H-Ras were controlled by modification with a caged compound in HVR under light irradiation.
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Affiliation(s)
- Rufiat Nahar
- Department of Bioinformatics, Graduate School of Engineering, Soka University, Hachioji, Tokyo 192-8577, Japan
| | - Seigo Iwata
- Department of Bioinformatics, Graduate School of Engineering, Soka University, Hachioji, Tokyo 192-8577, Japan
| | - Daiki Morita
- Department of Biomolecular Engineering, Graduate School of Engineering, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8603
| | - Yuhei Tahara
- Department of Biology, Graduate School of Science, Osaka City University, Sumiyoshi-ku, Osaka 558-8585, Japan
| | - Yasunobu Sugimoto
- Department of Biomolecular Engineering, Graduate School of Engineering, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8603.,Nagoya University Synchrotron Radiation Research Center, Furo-cho Chikusa-ku, Nagoya 464-8603, Japan
| | - Makoto Miyata
- Department of Biology, Graduate School of Science, Osaka City University, Sumiyoshi-ku, Osaka 558-8585, Japan
| | - Shinsaku Maruta
- Department of Bioinformatics, Graduate School of Engineering, Soka University, Hachioji, Tokyo 192-8577, Japan
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28
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Coley AB, Ward A, Keeton AB, Chen X, Maxuitenko Y, Prakash A, Li F, Foote JB, Buchsbaum DJ, Piazza GA. Pan-RAS inhibitors: Hitting multiple RAS isozymes with one stone. Adv Cancer Res 2021; 153:131-168. [PMID: 35101229 DOI: 10.1016/bs.acr.2021.07.009] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Mutations in the three RAS oncogenes are present in approximately 30% of all human cancers that drive tumor growth and metastasis by aberrant activation of RAS-mediated signaling. Despite the well-established role of RAS in tumorigenesis, past efforts to develop small molecule inhibitors have failed for various reasons leading many to consider RAS as "undruggable." Advances over the past decade with KRAS(G12C) mutation-specific inhibitors have culminated in the first FDA-approved RAS drug, sotorasib. However, the patient population that stands to benefit from KRAS(G12C) inhibitors is inherently limited to those patients harboring KRAS(G12C) mutations. Additionally, both intrinsic and acquired mechanisms of resistance have been reported that indicate allele-specificity may afford disadvantages. For example, the compensatory activation of uninhibited wild-type (WT) NRAS and HRAS isozymes can rescue cancer cells harboring KRAS(G12C) mutations from allele-specific inhibition or the occurrence of other mutations in KRAS. It is therefore prudent to consider alternative drug discovery strategies that may overcome these potential limitations. One such approach is pan-RAS inhibition, whereby all RAS isozymes co-expressed in the tumor cell population are targeted by a single inhibitor to block constitutively activated RAS regardless of the underlying mutation. This chapter provides a review of past and ongoing strategies to develop pan-RAS inhibitors in detail and seeks to outline the trajectory of this promising strategy of RAS inhibition.
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Affiliation(s)
- Alexander B Coley
- Department of Pharmacology, University of South Alabama, Mobile, AL, United States; Mitchell Cancer Institute, Mobile, AL, United States
| | - Antonio Ward
- Department of Pharmacology, University of South Alabama, Mobile, AL, United States; Mitchell Cancer Institute, Mobile, AL, United States
| | - Adam B Keeton
- Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL, United States
| | - Xi Chen
- Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL, United States
| | - Yulia Maxuitenko
- Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL, United States
| | - Aishwarya Prakash
- Mitchell Cancer Institute, Mobile, AL, United States; Department of Biochemistry & Molecular Biology, University of South Alabama, Mobile, AL, United States
| | - Feng Li
- Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL, United States
| | - Jeremy B Foote
- Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Donald J Buchsbaum
- Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Gary A Piazza
- Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL, United States.
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29
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de Castro CPM, Cadefau M, Cuartero S. The Mutational Landscape of Myeloid Leukaemia in Down Syndrome. Cancers (Basel) 2021; 13:4144. [PMID: 34439298 PMCID: PMC8394284 DOI: 10.3390/cancers13164144] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2021] [Revised: 07/30/2021] [Accepted: 08/11/2021] [Indexed: 12/12/2022] Open
Abstract
Children with Down syndrome (DS) are particularly prone to haematopoietic disorders. Paediatric myeloid malignancies in DS occur at an unusually high frequency and generally follow a well-defined stepwise clinical evolution. First, the acquisition of mutations in the GATA1 transcription factor gives rise to a transient myeloproliferative disorder (TMD) in DS newborns. While this condition spontaneously resolves in most cases, some clones can acquire additional mutations, which trigger myeloid leukaemia of Down syndrome (ML-DS). These secondary mutations are predominantly found in chromatin and epigenetic regulators-such as cohesin, CTCF or EZH2-and in signalling mediators of the JAK/STAT and RAS pathways. Most of them are also found in non-DS myeloid malignancies, albeit at extremely different frequencies. Intriguingly, mutations in proteins involved in the three-dimensional organization of the genome are found in nearly 50% of cases. How the resulting mutant proteins cooperate with trisomy 21 and mutant GATA1 to promote ML-DS is not fully understood. In this review, we summarize and discuss current knowledge about the sequential acquisition of genomic alterations in ML-DS.
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Affiliation(s)
| | - Maria Cadefau
- Josep Carreras Leukaemia Research Institute (IJC), Campus Can Ruti, 08916 Badalona, Spain; (C.P.M.d.C); (M.C.)
- Germans Trias i Pujol Research Institute (IGTP), Campus Can Ruti, 08916 Badalona, Spain
| | - Sergi Cuartero
- Josep Carreras Leukaemia Research Institute (IJC), Campus Can Ruti, 08916 Badalona, Spain; (C.P.M.d.C); (M.C.)
- Germans Trias i Pujol Research Institute (IGTP), Campus Can Ruti, 08916 Badalona, Spain
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30
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Jurado M, Castaño Ó, Zorzano A. Stochastic modulation evidences a transitory EGF-Ras-ERK MAPK activity induced by PRMT5. Comput Biol Med 2021; 133:104339. [PMID: 33910125 DOI: 10.1016/j.compbiomed.2021.104339] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Revised: 03/06/2021] [Accepted: 03/10/2021] [Indexed: 02/07/2023]
Abstract
The extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) pathway involves a three-step cascade of kinases that transduce signals and promote processes such as cell growth, development, and apoptosis. An aberrant response of this pathway is related to the proliferation of cell diseases and tumors. By using simulation modeling, we document that the protein arginine methyltransferase 5 (PRMT5) modulates the MAPK pathway and thus avoids an aberrant behavior. PRMT5 methylates the Raf kinase, reducing its catalytic activity and thereby, reducing the activation of ERK in time and amplitude. Two minimal computational models of the epidermal growth factor (EGF)-Ras-ERK MAPK pathway influenced by PRMT5 were proposed: a first model in which PRMT5 is activated by EGF and a second one in which PRMT5 is stimulated by the cascade response. The reported results show that PRMT5 reduces the time duration and the expression of the activated ERK in both cases, but only in the first model PRMT5 limits the EGF range that generates an ERK activation. Based on our data, we propose the protein PRMT5 as a regulatory factor to develop strategies to fight against an excessive activity of the MAPK pathway, which could be of use in chronic diseases and cancer.
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Affiliation(s)
- Manuel Jurado
- Biotechnology Ph.D. Programme, Faculty of Pharmacy, University of Barcelona, Barcelona, Spain
| | - Óscar Castaño
- Electronics and Biomedical Engineering, University of Barcelona, Barcelona, Spain; Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, Barcelona, Spain; CIBER in Bioengineering, Biomaterials and Nanomedicine, CIBER-BBN, Madrid, Spain; Bioelectronics Unit and Nanobioengineering Lab., Institute for Nanoscience and Nanotechnology of the University of Barcelona (IN2UB), Barcelona, Spain.
| | - Antonio Zorzano
- Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain; CIBER of Diabetes and Associated Metabolic Diseases, Barcelona, Spain; Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, University of Barcelona, Barcelona, Spain
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31
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O'Brien VP, Koehne AL, Dubrulle J, Rodriguez AE, Leverich CK, Kong VP, Campbell JS, Pierce RH, Goldenring JR, Choi E, Salama NR. Sustained Helicobacter pylori infection accelerates gastric dysplasia in a mouse model. Life Sci Alliance 2021; 4:e202000967. [PMID: 33310760 PMCID: PMC7768197 DOI: 10.26508/lsa.202000967] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Revised: 11/23/2020] [Accepted: 11/24/2020] [Indexed: 12/12/2022] Open
Abstract
More than 80% of gastric cancer is attributable to stomach infection with Helicobacter pylori (Hp). Gastric preneoplastic progression involves sequential tissue changes, including loss of parietal cells, metaplasia and dysplasia. In transgenic mice, active KRAS expression recapitulates these tissue changes in the absence of Hp infection. This model provides an experimental system to investigate additional roles of Hp in preneoplastic progression, beyond its known role in initiating inflammation. Tissue histology, gene expression, the immune cell repertoire, and metaplasia and dysplasia marker expression were assessed in KRAS+ mice +/-Hp infection. Hp+/KRAS+ mice had severe T-cell infiltration and altered macrophage polarization; a different trajectory of metaplasia; more dysplastic glands; and greater proliferation of metaplastic and dysplastic glands. Eradication of Hp with antibiotics, even after onset of metaplasia, prevented or reversed these tissue phenotypes. These results suggest that gastric preneoplastic progression differs between Hp+ and Hp- cases, and that sustained Hp infection can promote the later stages of gastric preneoplastic progression.
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Affiliation(s)
- Valerie P O'Brien
- Fred Hutchinson Cancer Research Center, Human Biology Division, Seattle, WA, USA
| | - Amanda L Koehne
- Fred Hutchinson Cancer Research Center, Comparative Medicine Shared Resource, Seattle, WA, USA
- Fred Hutchinson Cancer Research Center, Experimental Histopathology Shared Resource, Seattle, WA, USA
| | - Julien Dubrulle
- Fred Hutchinson Cancer Research Center, Genomics and Bioinformatics Shared Resource, Seattle, WA, USA
| | - Armando E Rodriguez
- Fred Hutchinson Cancer Research Center, Human Biology Division, Seattle, WA, USA
| | - Christina K Leverich
- Fred Hutchinson Cancer Research Center, Human Biology Division, Seattle, WA, USA
| | - V Paul Kong
- Fred Hutchinson Cancer Research Center, Experimental Histopathology Shared Resource, Seattle, WA, USA
| | - Jean S Campbell
- Fred Hutchinson Cancer Research Center, Program in Immunology, Seattle, WA, USA
| | - Robert H Pierce
- Fred Hutchinson Cancer Research Center, Program in Immunology, Seattle, WA, USA
| | - James R Goldenring
- Department of Surgery, Epithelial Biology Center, Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA
- Nashville Veterans Affairs Medical Center, Nashville, TN, USA
| | - Eunyoung Choi
- Department of Surgery, Epithelial Biology Center, Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Nina R Salama
- Fred Hutchinson Cancer Research Center, Human Biology Division, Seattle, WA, USA
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32
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Liu JF, Chen PC, Chang TM, Hou CH. Monocyte Chemoattractant Protein-1 promotes cancer cell migration via c-Raf/MAPK/AP-1 pathway and MMP-9 production in osteosarcoma. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2020; 39:254. [PMID: 33228783 PMCID: PMC7684958 DOI: 10.1186/s13046-020-01756-y] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Accepted: 10/30/2020] [Indexed: 01/07/2023]
Abstract
Background Osteosarcoma is generally reported among younger individuals and has a very poor prognosis, particularly for the development of metastasis. However, more effective metastatic biomarkers and therapeutic methods are absent. Monocyte chemoattractant protein-1 (MCP-1) is involved in cancer progression and inflammatory recruitment. Although previous studies have reported higher serum MCP-1 levels in patients with osteosarcoma, the role of MCP-1 in osteosarcoma progression remains to be addressed. Methods The osteosarcoma cell migratory ability was assessed by transwell migration assay. The MCP-1 and MMP-9 expression levels were analyzed by Western blot and qPCR. The signal activation was conducted by Western blot. The in vivo mouse experiment and tumor tissue array were performed to confirm our findings in vitro. Results The present study demonstrates that MCP-1 regulates cell mobility through matrix metalloproteinase (MMP)-9 expression in osteosarcoma cells. Moreover, MCP-1 promotes MMP-9 expression, cell migration, and cell invasion by mediating CCR2, c-Raf, MAPK, and AP-1 signal transduction. Using MCP-1 knockdown stable cell lines, we found that MCP-1 knockdown reduces MMP-9 expression and cell mobility. Finally, we found high MCP-1 expression levels in osteosarcoma specimens. Conclusions Our results provide prognostic value of MCP-1 in osteosarcoma by promoting MMP-9 expression. Supplementary Information The online version contains supplementary material available at 10.1186/s13046-020-01756-y.
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Affiliation(s)
- Ju-Fang Liu
- School of Oral Hygiene, College of Oral Medicine, Taipei Medical University, Taipei, 110, Taiwan
| | - Po-Chun Chen
- Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, 40447, Taiwan.,Translational medicine center, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei City, 11101, Taiwan.,Department of Biotechnology, College of Medical and Health Science, Asia University, Taichung, 41354, Taiwan
| | - Tsung-Ming Chang
- School of Medicine, Institute of Physiology, National Yang-Ming University, Taipei City, 11221, Taiwan
| | - Chun-Han Hou
- Department of Orthopedic Surgery, National Taiwan University Hospital, 100, NO. 1, Jen-Ai Road, Taipei City, 11102, Taiwan, ROC.
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33
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Valencia-Sama I, Ladumor Y, Kee L, Adderley T, Christopher G, Robinson CM, Kano Y, Ohh M, Irwin MS. NRAS Status Determines Sensitivity to SHP2 Inhibitor Combination Therapies Targeting the RAS-MAPK Pathway in Neuroblastoma. Cancer Res 2020; 80:3413-3423. [PMID: 32586982 DOI: 10.1158/0008-5472.can-19-3822] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Revised: 04/08/2020] [Accepted: 06/22/2020] [Indexed: 11/16/2022]
Abstract
Survival for high-risk neuroblastoma remains poor and treatment for relapsed disease rarely leads to long-term cures. Large sequencing studies of neuroblastoma tumors from diagnosis have not identified common targetable driver mutations other than the 10% of tumors that harbor mutations in the anaplastic lymphoma kinase (ALK) gene. However, at neuroblastoma recurrence, more frequent mutations in genes in the RAS-MAPK pathway have been detected. The PTPN11-encoded tyrosine phosphatase SHP2 is an activator of the RAS pathway, and we and others have shown that pharmacologic inhibition of SHP2 suppresses the growth of various tumor types harboring KRAS mutations such as pancreatic and lung cancers. Here we report inhibition of growth and downstream RAS-MAPK signaling in neuroblastoma cells in response to treatment with the SHP2 inhibitors SHP099, II-B08, and RMC-4550. However, neuroblastoma cell lines harboring endogenous NRAS Q61K mutation (which is commonly detected at relapse) or isogenic neuroblastoma cells engineered to overexpress NRASQ61K were distinctly resistant to SHP2 inhibitors. Combinations of SHP2 inhibitors with other RAS pathway inhibitors such as trametinib, vemurafenib, and ulixertinib were synergistic and reversed resistance to SHP2 inhibition in neuroblastoma in vitro and in vivo. These results suggest for the first time that combination therapies targeting SHP2 and other components of the RAS-MAPK pathway may be effective against conventional therapy-resistant relapsed neuroblastoma, including those that have acquired NRAS mutations. SIGNIFICANCE: These findings suggest that conventional therapy-resistant, relapsed neuroblastoma may be effectively treated via combined inhibition of SHP2 and MEK or ERK of the RAS-MAPK pathway.
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Affiliation(s)
- Ivette Valencia-Sama
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.,Cell Biology Program, The Hospital for Sick Children, Toronto, Canada
| | - Yagnesh Ladumor
- Cell Biology Program, The Hospital for Sick Children, Toronto, Canada.,Department of Medical Biophysics, University of Toronto, Toronto, Canada
| | - Lynn Kee
- Cell Biology Program, The Hospital for Sick Children, Toronto, Canada
| | - Teresa Adderley
- Cell Biology Program, The Hospital for Sick Children, Toronto, Canada
| | | | - Claire M Robinson
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.,Department of Biochemistry, University of Toronto, Toronto, Canada
| | - Yoshihito Kano
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.,Department of Biochemistry, University of Toronto, Toronto, Canada.,Department of Clinical Oncology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Michael Ohh
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada. .,Department of Biochemistry, University of Toronto, Toronto, Canada
| | - Meredith S Irwin
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada. .,Cell Biology Program, The Hospital for Sick Children, Toronto, Canada.,Department of Medical Biophysics, University of Toronto, Toronto, Canada.,Department of Pediatrics, The Hospital for Sick Children, Toronto, Canada
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34
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Salgia R, Mambetsariev I, Tan T, Schwer A, Pearlstein DP, Chehabi H, Baroz A, Fricke J, Pharaon R, Romo H, Waddington T, Babikian R, Buck L, Kulkarni P, Cianfrocca M, Djulbegovic B, Pal SK. Complex Oncological Decision-Making Utilizing Fast-and-Frugal Trees in a Community Setting-Role of Academic and Hybrid Modeling. J Clin Med 2020; 9:E1884. [PMID: 32560187 PMCID: PMC7356888 DOI: 10.3390/jcm9061884] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Revised: 06/11/2020] [Accepted: 06/12/2020] [Indexed: 12/24/2022] Open
Abstract
Non-small cell lung cancer is a devastating disease and with the advent of targeted therapies and molecular testing, the decision-making process has become complex. While established guidelines and pathways offer some guidance, they are difficult to utilize in a busy community practice and are not always implemented in the community. The rationale of the study was to identify a cohort of patients with lung adenocarcinoma at a City of Hope community site (n = 11) and utilize their case studies to develop a decision-making framework utilizing fast-and-frugal tree (FFT) heuristics. Most patients had stage IV (N = 9, 81.8%) disease at the time of the first consultation. The most common symptoms at initial presentation were cough (N = 5, 45.5%), shortness of breath (N = 3, 27.2%), and weight loss (N = 3, 27.2%). The Eastern Cooperative Oncology Group (ECOG) performance status ranged from 0-1 in all patients in this study. Distribution of molecular drivers among the patients were as follows: EGFR (N = 5, 45.5%), KRAS (N = 2, 18.2%), ALK (N = 2, 18.2%), MET (N = 2, 18.2%), and RET (N = 1, 9.1%). Seven initial FFTs were developed for the various case scenarios, but ultimately the decisions were condensed into one FFT, a molecular stage IV FFT, that arrived at accurate decisions without sacrificing initial information. While these FFT decision trees may seem arbitrary to an experienced oncologist at an academic site, the simplicity of their utility is essential for community practice where patients often do not get molecular testing and are not assigned proper therapy.
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Affiliation(s)
- Ravi Salgia
- Department of Medical Oncology and Therapeutics Research, 1500 E Duarte Road, City of Hope National Medical Center, Duarte, CA 91010, USA; (I.M.); (T.T.); (A.B.); (J.F.); (R.P.); (H.R.); (R.B.); (L.B.); (P.K.); (M.C.); (S.K.P.)
| | - Isa Mambetsariev
- Department of Medical Oncology and Therapeutics Research, 1500 E Duarte Road, City of Hope National Medical Center, Duarte, CA 91010, USA; (I.M.); (T.T.); (A.B.); (J.F.); (R.P.); (H.R.); (R.B.); (L.B.); (P.K.); (M.C.); (S.K.P.)
| | - Tingting Tan
- Department of Medical Oncology and Therapeutics Research, 1500 E Duarte Road, City of Hope National Medical Center, Duarte, CA 91010, USA; (I.M.); (T.T.); (A.B.); (J.F.); (R.P.); (H.R.); (R.B.); (L.B.); (P.K.); (M.C.); (S.K.P.)
| | - Amanda Schwer
- Newport Diagnostic Center, Newport Beach, CA 92660, USA; (A.S.); (H.C.)
| | | | - Hazem Chehabi
- Newport Diagnostic Center, Newport Beach, CA 92660, USA; (A.S.); (H.C.)
| | - Angel Baroz
- Department of Medical Oncology and Therapeutics Research, 1500 E Duarte Road, City of Hope National Medical Center, Duarte, CA 91010, USA; (I.M.); (T.T.); (A.B.); (J.F.); (R.P.); (H.R.); (R.B.); (L.B.); (P.K.); (M.C.); (S.K.P.)
| | - Jeremy Fricke
- Department of Medical Oncology and Therapeutics Research, 1500 E Duarte Road, City of Hope National Medical Center, Duarte, CA 91010, USA; (I.M.); (T.T.); (A.B.); (J.F.); (R.P.); (H.R.); (R.B.); (L.B.); (P.K.); (M.C.); (S.K.P.)
| | - Rebecca Pharaon
- Department of Medical Oncology and Therapeutics Research, 1500 E Duarte Road, City of Hope National Medical Center, Duarte, CA 91010, USA; (I.M.); (T.T.); (A.B.); (J.F.); (R.P.); (H.R.); (R.B.); (L.B.); (P.K.); (M.C.); (S.K.P.)
| | - Hannah Romo
- Department of Medical Oncology and Therapeutics Research, 1500 E Duarte Road, City of Hope National Medical Center, Duarte, CA 91010, USA; (I.M.); (T.T.); (A.B.); (J.F.); (R.P.); (H.R.); (R.B.); (L.B.); (P.K.); (M.C.); (S.K.P.)
| | - Thomas Waddington
- Department of Medicine, City of Hope National Medical Center, Duarte, CA 91010, USA;
| | - Razmig Babikian
- Department of Medical Oncology and Therapeutics Research, 1500 E Duarte Road, City of Hope National Medical Center, Duarte, CA 91010, USA; (I.M.); (T.T.); (A.B.); (J.F.); (R.P.); (H.R.); (R.B.); (L.B.); (P.K.); (M.C.); (S.K.P.)
| | - Linda Buck
- Department of Medical Oncology and Therapeutics Research, 1500 E Duarte Road, City of Hope National Medical Center, Duarte, CA 91010, USA; (I.M.); (T.T.); (A.B.); (J.F.); (R.P.); (H.R.); (R.B.); (L.B.); (P.K.); (M.C.); (S.K.P.)
| | - Prakash Kulkarni
- Department of Medical Oncology and Therapeutics Research, 1500 E Duarte Road, City of Hope National Medical Center, Duarte, CA 91010, USA; (I.M.); (T.T.); (A.B.); (J.F.); (R.P.); (H.R.); (R.B.); (L.B.); (P.K.); (M.C.); (S.K.P.)
| | - Mary Cianfrocca
- Department of Medical Oncology and Therapeutics Research, 1500 E Duarte Road, City of Hope National Medical Center, Duarte, CA 91010, USA; (I.M.); (T.T.); (A.B.); (J.F.); (R.P.); (H.R.); (R.B.); (L.B.); (P.K.); (M.C.); (S.K.P.)
| | - Benjamin Djulbegovic
- Department of Hematology & Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA 91010, USA;
| | - Sumanta K. Pal
- Department of Medical Oncology and Therapeutics Research, 1500 E Duarte Road, City of Hope National Medical Center, Duarte, CA 91010, USA; (I.M.); (T.T.); (A.B.); (J.F.); (R.P.); (H.R.); (R.B.); (L.B.); (P.K.); (M.C.); (S.K.P.)
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Ding XW, Li R, Geetha T, Tao YX, Babu JR. Nerve growth factor in metabolic complications and Alzheimer's disease: Physiology and therapeutic potential. Biochim Biophys Acta Mol Basis Dis 2020; 1866:165858. [PMID: 32531260 DOI: 10.1016/j.bbadis.2020.165858] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2020] [Revised: 05/11/2020] [Accepted: 06/02/2020] [Indexed: 02/07/2023]
Abstract
As the population ages, obesity and metabolic complications as well as neurological disorders are becoming more prevalent, with huge economic burdens on both societies and families. New therapeutics are urgently needed. Nerve growth factor (NGF), first discovered in 1950s, is a neurotrophic factor involved in regulating cell proliferation, growth, survival, and apoptosis in both central and peripheral nervous systems. NGF and its precursor, proNGF, bind to TrkA and p75 receptors and initiate protein phosphorylation cascades, resulting in changes of cellular functions, and are associated with obesity, diabetes and its complications, and Alzheimer's disease. In this article, we summarize changes in NGF levels in metabolic and neuronal disorders, the signal transduction initiated by NGF and proNGF, the physiological and pathophysiological relevance, and therapeutic potential in treating chronic metabolic diseases and cognitive decline.
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Affiliation(s)
- Xiao-Wen Ding
- Department of Nutrition, Dietetics, and Hospitality Management, Auburn University, Auburn, AL 36849, USA
| | - Rongzi Li
- Department of Nutrition, Dietetics, and Hospitality Management, Auburn University, Auburn, AL 36849, USA
| | - Thangiah Geetha
- Department of Nutrition, Dietetics, and Hospitality Management, Auburn University, Auburn, AL 36849, USA; Boshell Metabolic Diseases and Diabetes Program, Auburn University, Auburn, AL 36849, USA
| | - Ya-Xiong Tao
- Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA.
| | - Jeganathan Ramesh Babu
- Department of Nutrition, Dietetics, and Hospitality Management, Auburn University, Auburn, AL 36849, USA; Boshell Metabolic Diseases and Diabetes Program, Auburn University, Auburn, AL 36849, USA.
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Abstract
Lung cancer is a heterogeneous genomic disease. Smoking remains the primary cause. Genetic susceptibility and environmental exposures are responsible for 10% to 15% of cases. Targeted therapies improve survival in patients with tumors with oncogenic drivers. It is critical to expand our understanding of genetic alterations in non-small cell lung cancer to increase the available targeted therapies. Alterations beyond epidermal growth factor receptor (EGFR), ALK, and ROS1 exemplify lung cancer's complexity and the need for investments in precision therapy to extend patient survival and improve outcomes. This article covers genetic targets beyond EGFR, ALK and ROS1, their novel agents, challenges, and future directions.
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Affiliation(s)
- Karen L Reckamp
- Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA.
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Muratcioglu S, Aydin C, Odabasi E, Ozdemir ES, Firat-Karalar EN, Jang H, Tsai CJ, Nussinov R, Kavakli IH, Gursoy A, Keskin O. Oncogenic K-Ras4B Dimerization Enhances Downstream Mitogen-activated Protein Kinase Signaling. J Mol Biol 2020; 432:1199-1215. [PMID: 31931009 PMCID: PMC8533050 DOI: 10.1016/j.jmb.2020.01.002] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Revised: 12/31/2019] [Accepted: 01/07/2020] [Indexed: 02/07/2023]
Abstract
Ras recruits and activates effectors that transmit receptor-initiated signals. Monomeric Ras can bind Raf; however, Raf's activation requires dimerization, which can be facilitated by Ras dimerization. Previously, we showed that active K-Ras4B dimerizes in silico and in vitro through two major interfaces: (i) β-interface, mapped to Switch I and effector-binding regions, (ii) α-interface at the allosteric lobe. Here, we chose constitutively active K-Ras4B as our control and two double mutants (K101D and R102E; and R41E and K42D) in the α- and β-interfaces. Two of the mutations are from The Cancer Genome Atlas (TCGA) and the Catalogue Of Somatic Mutations In Cancer (COSMIC) data sets. R41 and R102 are found in several adenocarcinomas in Ras isoforms. We performed site-directed mutagenesis, cellular localization experiments, and molecular dynamics (MD) simulations to assess the impact of the mutations on K-Ras4B dimerization and function. α-interface K101D/R102E double mutations reduced dimerization but only slightly reduced downstream phosphorylated extracellular signal-regulated kinase (ERK) (pERK) levels. While β-interface R41E/K42D double mutations did not interfere with dimerization, they almost completely blocked K-Ras4B-mediated ERK phosphorylation. Both double mutations increased downstream phosphorylated Akt (pAkt) levels in cells. Changes in pERK and pAkt levels altered ERK- and Akt-regulated gene expressions, such as EGR1, JUN, and BCL2L11. These results underscore the role of the α-interface in K-Ras4B homodimerization and the β-surface in effector binding. MD simulations highlight that the membrane and hypervariable region (HVR) interact with both α- and β-interfaces of K-Ras4B mutants, respectively, inhibiting homodimerization and probably effector binding. Mutations at both interfaces interfered with mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase signaling but in different forms and extents. We conclude that dimerization is not necessary but enhances downstream MAPK signaling.
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Affiliation(s)
- Serena Muratcioglu
- Departments of Chemical and Biological Engineering, Research Center for Translational Medicine, Koc University, Istanbul 34450, Turkey
| | - Cihan Aydin
- Departments of Chemical and Biological Engineering, Research Center for Translational Medicine, Koc University, Istanbul 34450, Turkey
| | - Ezgi Odabasi
- Departments of Molecular Biology and Genetics, Koc University, Istanbul 34450, Turkey
| | - E Sila Ozdemir
- Departments of Chemical and Biological Engineering, Research Center for Translational Medicine, Koc University, Istanbul 34450, Turkey
| | | | - Hyunbum Jang
- Computational Structural Biology Section, Frederick National Laboratory for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702, USA
| | - Chung-Jung Tsai
- Computational Structural Biology Section, Frederick National Laboratory for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702, USA
| | - Ruth Nussinov
- Computational Structural Biology Section, Frederick National Laboratory for Cancer Research, National Cancer Institute at Frederick, Frederick, MD 21702, USA; Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel
| | - Ibrahim Halil Kavakli
- Departments of Chemical and Biological Engineering, Research Center for Translational Medicine, Koc University, Istanbul 34450, Turkey; Departments of Molecular Biology and Genetics, Koc University, Istanbul 34450, Turkey
| | - Attila Gursoy
- Departments of Computer Engineering, Research Center for Translational Medicine, Koc University, Istanbul 34450, Turkey.
| | - Ozlem Keskin
- Departments of Chemical and Biological Engineering, Research Center for Translational Medicine, Koc University, Istanbul 34450, Turkey.
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Dubois F, Bergot E, Zalcman G, Levallet G. RASSF1A, puppeteer of cellular homeostasis, fights tumorigenesis, and metastasis-an updated review. Cell Death Dis 2019; 10:928. [PMID: 31804463 PMCID: PMC6895193 DOI: 10.1038/s41419-019-2169-x] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Revised: 11/19/2019] [Accepted: 11/20/2019] [Indexed: 12/27/2022]
Abstract
The Ras association domain family protein1 isoform A (RASSF1A) is a well-known tumor-suppressor protein frequently inactivated in various human cancers. Consistent with its function as a molecular scaffold protein, referred to in many studies, RASSF1A prevents initiation of tumorigenesis, growth, and dissemination through different biological functions, including cell cycle arrest, migration/metastasis inhibition, microtubular stabilization, and apoptosis promotion. As a regulator of key cancer pathways, namely Ras/Rho GTPases and Hippo signaling without ignoring strong interaction with microtubules, RASSF1A is indeed one of the guardians of cell homeostasis. To date, as we approach the two decade anniversary of RASSF1A's discovery, this review will summarize our current knowledge on the RASSF1A key interactions as a tumor suppressor and discuss their impact on cell fate during carcinogenesis. This could facilitate a deeper understanding of tumor development and provide us with new strategies in cancer treatment by targeting the RASSF1A pathway.
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Affiliation(s)
- Fatéméh Dubois
- Normandie University, UNICAEN, CEA, CNRS, ISTCT/CERVOxy group, GIP CYCERON, Caen, France
- Department of Pathology, CHU de Caen, Caen, France
| | - Emmanuel Bergot
- Normandie University, UNICAEN, CEA, CNRS, ISTCT/CERVOxy group, GIP CYCERON, Caen, France
- Department of Pulmonology & Thoracic Oncology, CHU de Caen, Caen, France
| | - Gérard Zalcman
- U830 INSERM "Genetics and biology of cancers, A.R.T group", Curie Institute, Paris, France
- Department of Thoracic Oncology & CIC1425, Hôpital Bichat-Claude Bernard, Assistance Publique Hôpitaux de Paris, Université Paris-Diderot, Paris, France
| | - Guénaëlle Levallet
- Normandie University, UNICAEN, CEA, CNRS, ISTCT/CERVOxy group, GIP CYCERON, Caen, France.
- Department of Pathology, CHU de Caen, Caen, France.
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He H, Xu C, Cheng Z, Qian X, Zheng L. Drug Combinatorial Therapies for the Treatment of KRAS Mutated Lung Cancers. Curr Top Med Chem 2019; 19:2128-2142. [PMID: 31475900 DOI: 10.2174/1568026619666190902150555] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Revised: 06/23/2019] [Accepted: 07/04/2019] [Indexed: 02/08/2023]
Abstract
KRAS is the most common oncogene to be mutated in lung cancer, and therapeutics directly targeting KRAS have proven to be challenging. The mutations of KRAS are associated with poor prognosis, and resistance to both adjuvant therapy and targeted EGFR TKI. EGFR TKIs provide significant clinical benefit for patients whose tumors bear EGFR mutations. However, tumors with KRAS mutations rarely respond to the EGFR TKI therapy. Thus, combination therapy is essential for the treatment of lung cancers with KRAS mutations. EGFR TKI combined with inhibitors of MAPKs, PI3K/mTOR, HDAC, Wee1, PARP, CDK and Hsp90, even miRNAs and immunotherapy, were reviewed. Although the effects of the combination vary, the combined therapeutics are one of the best options at present to treat KRAS mutant lung cancer.
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Affiliation(s)
- Hao He
- School of Pharmacy, Xi'an Medical University, Xi'an, Shaanxi, China
| | - Chang Xu
- National Vaccine & Serum Institute, Beijing, China
| | - Zhao Cheng
- School of Pharmacy, Xi'an Medical University, Xi'an, Shaanxi, China
| | - Xiaoying Qian
- School of Pharmacy, Xi'an Medical University, Xi'an, Shaanxi, China
| | - Lei Zheng
- School of Pharmacy, Xi'an Medical University, Xi'an, Shaanxi, China
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40
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Erber J, Steiner JD, Isensee J, Lobbes LA, Toschka A, Beleggia F, Schmitt A, Kaiser RWJ, Siedek F, Persigehl T, Hucho T, Reinhardt HC. Dual Inhibition of GLUT1 and the ATR/CHK1 Kinase Axis Displays Synergistic Cytotoxicity in KRAS-Mutant Cancer Cells. Cancer Res 2019; 79:4855-4868. [PMID: 31405847 DOI: 10.1158/0008-5472.can-18-3959] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Revised: 06/18/2019] [Accepted: 08/06/2019] [Indexed: 11/16/2022]
Abstract
The advent of molecularly targeted therapeutic agents has opened a new era in cancer therapy. However, many tumors rely on nondruggable cancer-driving lesions. In addition, long-lasting clinical benefits from single-agent therapies rarely occur, as most of the tumors acquire resistance over time. The identification of targeted combination regimens interfering with signaling through oncogenically rewired pathways provides a promising approach to enhance efficacy of single-agent-targeted treatments. Moreover, combination drug therapies might overcome the emergence of drug resistance. Here, we performed a focused flow cytometry-based drug synergy screen and identified a novel synergistic interaction between GLUT1-mediated glucose transport and the cell-cycle checkpoint kinases ATR and CHK1. Combined inhibition of CHK1/GLUT1 or ATR/GLUT1 robustly induced apoptosis, particularly in RAS-mutant cancer cells. Mechanistically, combined inhibition of ATR/CHK1 and GLUT1 arrested sensitive cells in S-phase and led to the accumulation of genotoxic damage, particularly in S-phase. In vivo, simultaneous inhibition of ATR and GLUT1 significantly reduced tumor volume gain in an autochthonous mouse model of KrasG12D -driven soft tissue sarcoma. Taken together, these findings pave the way for combined inhibition of GLUT1 and ATR/CHK1 as a therapeutic approach for KRAS-driven cancers. SIGNIFICANCE: Dual targeting of the DNA damage response and glucose transport synergistically induces apoptosis in KRAS-mutant cancer, suggesting this combination treatment for clinical validation in KRAS-stratified tumor patients.
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Affiliation(s)
- Johanna Erber
- Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Dusseldorf, Center for Molecular Medicine Cologne, CECAD, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
| | - Joachim D Steiner
- Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Dusseldorf, Center for Molecular Medicine Cologne, CECAD, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Jörg Isensee
- Translational Pain Research, Department of Anesthesiology and Intensive Care Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Leonard A Lobbes
- Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Dusseldorf, Center for Molecular Medicine Cologne, CECAD, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - André Toschka
- Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Dusseldorf, Center for Molecular Medicine Cologne, CECAD, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Filippo Beleggia
- Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Dusseldorf, Center for Molecular Medicine Cologne, CECAD, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Anna Schmitt
- Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Dusseldorf, Center for Molecular Medicine Cologne, CECAD, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Rainer W J Kaiser
- Department II of Internal Medicine and Center for Molecular Medicine Cologne, CECAD, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Florian Siedek
- Institute of Diagnostic and Interventional Radiology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Thorsten Persigehl
- Institute of Diagnostic and Interventional Radiology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Tim Hucho
- Translational Pain Research, Department of Anesthesiology and Intensive Care Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Hans C Reinhardt
- Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Dusseldorf, Center for Molecular Medicine Cologne, CECAD, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
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Kleczko EK, Kwak JW, Schenk EL, Nemenoff RA. Targeting the Complement Pathway as a Therapeutic Strategy in Lung Cancer. Front Immunol 2019; 10:954. [PMID: 31134065 PMCID: PMC6522855 DOI: 10.3389/fimmu.2019.00954] [Citation(s) in RCA: 81] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2019] [Accepted: 04/15/2019] [Indexed: 12/20/2022] Open
Abstract
Lung cancer is the leading cause of cancer death in men and women. Lung adenocarcinoma (LUAD), represents approximately 40% of all lung cancer cases. Advances in recent years, such as the identification of oncogenes and the use of immunotherapies, have changed the treatment of LUAD. Yet survival rates still remain low. Additionally, there is still a gap in understanding the molecular and cellular interactions between cancer cells and the immune tumor microenvironment (TME). Defining how cancer cells with distinct oncogenic drivers interact with the TME and new strategies for enhancing anti-tumor immunity are greatly needed. The complement cascade, a central part of the innate immune system, plays an important role in regulation of adaptive immunity. Initially it was proposed that complement activation on the surface of cancer cells would inhibit cancer progression via membrane attack complex (MAC)-dependent killing. However, data from several groups have shown that complement activation promotes cancer progression, probably through the actions of anaphylatoxins (C3a and C5a) on the TME and engagement of immunoevasive pathways. While originally shown to be produced in the liver, recent studies show localized complement production in numerous cell types including immune cells and tumor cells. These results suggest that complement inhibitory drugs may represent a powerful new approach for treatment of NSCLC, and numerous new anti-complement drugs are in clinical development. However, the mechanisms by which complement is activated and affects tumor progression are not well understood. Furthermore, the role of local complement production vs. systemic activation has not been carefully examined. This review will focus on our current understanding of complement action in LUAD, and describe gaps in our knowledge critical for advancing complement therapy into the clinic.
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Affiliation(s)
- Emily K Kleczko
- Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Jeff W Kwak
- Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Erin L Schenk
- Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Raphael A Nemenoff
- Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
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42
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He B, Tran JT, Sanchez DJ. Manipulation of Type I Interferon Signaling by HIV and AIDS-Associated Viruses. J Immunol Res 2019; 2019:8685312. [PMID: 31089479 PMCID: PMC6476103 DOI: 10.1155/2019/8685312] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Accepted: 02/14/2019] [Indexed: 12/20/2022] Open
Abstract
Type I Interferons were first described for their profound antiviral abilities in cell culture and animal models, and later, they were translated into potent antiviral therapeutics. However, as additional studies into the function of Type I Interferons progressed, it was also seen that pathogenic viruses have coevolved to encode potent mechanisms allowing them to evade or suppress the impact of Type I Interferons on their replication. For chronic viral infections, such as HIV and many of the AIDS-associated viruses, including HTLV, HCV, KSHV, and EBV, the clinical efficacy of Type I Interferons is limited by these mechanisms. Here, we review some of the ways that HIV and AIDS-associated viruses thrive in Type I Interferon-rich environments via mechanisms that block the function of this important antiviral cytokine. Overall, a better understanding of these mechanisms creates avenues to better understand the innate immune response to these viruses as well as plan the development of antivirals that would allow the natural antiviral effect of Type I Interferons to manifest during these infections.
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Affiliation(s)
- Buyuan He
- Pharmaceutical Sciences Department, College of Pharmacy, Western University of Health Sciences, Pomona 91766, California, USA
| | - James T. Tran
- Pharmaceutical Sciences Department, College of Pharmacy, Western University of Health Sciences, Pomona 91766, California, USA
| | - David Jesse Sanchez
- Pharmaceutical Sciences Department, College of Pharmacy, Western University of Health Sciences, Pomona 91766, California, USA
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Lu B, Zhu DY, Yin JH, Xu H, Zhang CQ, Ke QF, Gao YS, Guo YP. Incorporation of cerium oxide in hollow mesoporous bioglass scaffolds for enhanced bone regeneration by activating the ERK signaling pathway. Biofabrication 2019; 11:025012. [PMID: 30754024 DOI: 10.1088/1758-5090/ab0676] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Hierarchically porous structures and bioactive compositions of artificial biomaterials play a positive role in bone defect healing and new bone regeneration. Herein, cerium oxide nanoparticles-modified bioglass (Ce-BG) scaffolds were firstly constructed by the incorporation of hollow mesoporous Ce-BG microspheres in CTS via a freeze-drying technology. The interconnected macropores in Ce-BG scaffolds facilitated the in-growth of bone cells/tissues from material surfaces into the interiors, while the hollow cores and mesopore shells in Ce-BG microspheres provides more active sites for bone mineralization. The cerium oxide nanoparticles in the scaffolds rapidly promoted the proliferation and osteogenic differentiation of human bone marrow-derived mesenchymal stem cells (hBMSCs), as confirmed by the up-regulation of osteogenesis-related markers such as OCN, ALP and COL-1. The enhanced osteoinductivity of Ce-BG scaffolds was mainly related to the activated ERK pathway, and it was blocked by adding a selective ERK1/2 inhibitor (SCH772984). In vivo rat cranial defect models revealed that Ce-BG scaffolds accelerated collagen deposition, osteoblast formation and bone regeneration as compared to BG scaffolds. The exciting results demonstrated that the synergistic effects between hierarchically porous structures and cerium oxide nanoparticles contributed to osteogenic ability, and hollow mesoporous Ce-BG scaffolds would be a novel platform for bone regeneration.
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Affiliation(s)
- Bin Lu
- The Education Ministry Key Lab of Resource Chemistry and Shanghai Key Laboratory of Rare Earth Functional Materials, Shanghai Normal University, Shanghai 200234, People's Republic of China
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Kano Y, Gebregiworgis T, Marshall CB, Radulovich N, Poon BPK, St-Germain J, Cook JD, Valencia-Sama I, Grant BMM, Herrera SG, Miao J, Raught B, Irwin MS, Lee JE, Yeh JJ, Zhang ZY, Tsao MS, Ikura M, Ohh M. Tyrosyl phosphorylation of KRAS stalls GTPase cycle via alteration of switch I and II conformation. Nat Commun 2019; 10:224. [PMID: 30644389 PMCID: PMC6333830 DOI: 10.1038/s41467-018-08115-8] [Citation(s) in RCA: 74] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2018] [Accepted: 12/17/2018] [Indexed: 12/27/2022] Open
Abstract
Deregulation of the RAS GTPase cycle due to mutations in the three RAS genes is commonly associated with cancer development. Protein tyrosine phosphatase SHP2 promotes RAF-to-MAPK signaling pathway and is an essential factor in RAS-driven oncogenesis. Despite the emergence of SHP2 inhibitors for the treatment of cancers harbouring mutant KRAS, the mechanism underlying SHP2 activation of KRAS signaling remains unclear. Here we report tyrosyl-phosphorylation of endogenous RAS and demonstrate that KRAS phosphorylation via Src on Tyr32 and Tyr64 alters the conformation of switch I and II regions, which stalls multiple steps of the GTPase cycle and impairs binding to effectors. In contrast, SHP2 dephosphorylates KRAS, a process that is required to maintain dynamic canonical KRAS GTPase cycle. Notably, Src- and SHP2-mediated regulation of KRAS activity extends to oncogenic KRAS and the inhibition of SHP2 disrupts the phosphorylation cycle, shifting the equilibrium of the GTPase cycle towards the stalled ‘dark state’. Deregulation of the RAS GTPase cycle due to mutations in RAS genes is commonly associated with cancer development. Here authors use NMR and mass spectrometry to shows that KRAS phosphorylation via Src alters the conformation of switch I and II regions and thereby impacts the GTPase cycle.
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Affiliation(s)
- Yoshihito Kano
- Department of Laboratory Medicine and Pathobiology, University of Toronto, 661 University Avenue, Toronto, ON, M5G 1M1, Canada.,Department of Biochemistry, University of Toronto, 661 University Avenue, Toronto, ON, M5G 1M1, Canada
| | - Teklab Gebregiworgis
- Princess Margaret Cancer Centre, University Health Network and Department of Medical Biophysics, University of Toronto, 101 College Street, Toronto, ON, M5G 1L7, Canada
| | - Christopher B Marshall
- Princess Margaret Cancer Centre, University Health Network and Department of Medical Biophysics, University of Toronto, 101 College Street, Toronto, ON, M5G 1L7, Canada
| | - Nikolina Radulovich
- Princess Margaret Cancer Centre, University Health Network and Department of Pathology, University of Toronto, Toronto, ON, M5G 1L7, Canada
| | - Betty P K Poon
- Department of Laboratory Medicine and Pathobiology, University of Toronto, 661 University Avenue, Toronto, ON, M5G 1M1, Canada
| | - Jonathan St-Germain
- Princess Margaret Cancer Centre, University Health Network and Department of Medical Biophysics, University of Toronto, 101 College Street, Toronto, ON, M5G 1L7, Canada
| | - Jonathan D Cook
- Department of Laboratory Medicine and Pathobiology, University of Toronto, 661 University Avenue, Toronto, ON, M5G 1M1, Canada
| | - Ivette Valencia-Sama
- Department of Laboratory Medicine and Pathobiology, University of Toronto, 661 University Avenue, Toronto, ON, M5G 1M1, Canada.,Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, 686 Bay Street, Toronto, ON, 5G OA4, Canada
| | - Benjamin M M Grant
- Princess Margaret Cancer Centre, University Health Network and Department of Medical Biophysics, University of Toronto, 101 College Street, Toronto, ON, M5G 1L7, Canada
| | - Silvia Gabriela Herrera
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, 27599, USA
| | - Jinmin Miao
- Department of Medicinal Chemistry and Molecular Pharmacology, Center for Cancer Research and Institute for Drug Discovery, Purdue University, 720 Clinic Drive, West Lafayette, IN, 47907, USA
| | - Brian Raught
- Princess Margaret Cancer Centre, University Health Network and Department of Medical Biophysics, University of Toronto, 101 College Street, Toronto, ON, M5G 1L7, Canada
| | - Meredith S Irwin
- Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, 686 Bay Street, Toronto, ON, 5G OA4, Canada
| | - Jeffrey E Lee
- Department of Laboratory Medicine and Pathobiology, University of Toronto, 661 University Avenue, Toronto, ON, M5G 1M1, Canada
| | - Jen Jen Yeh
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, 27599, USA.,Department of Surgery, University of North Carolina, Chapel Hill, NC, 27599, USA.,Department of Pharmacology, University of North Carolina, Chapel Hill, NC, 27599, USA
| | - Zhong-Yin Zhang
- Department of Medicinal Chemistry and Molecular Pharmacology, Center for Cancer Research and Institute for Drug Discovery, Purdue University, 720 Clinic Drive, West Lafayette, IN, 47907, USA
| | - Ming-Sound Tsao
- Princess Margaret Cancer Centre, University Health Network and Department of Pathology, University of Toronto, Toronto, ON, M5G 1L7, Canada
| | - Mitsuhiko Ikura
- Princess Margaret Cancer Centre, University Health Network and Department of Medical Biophysics, University of Toronto, 101 College Street, Toronto, ON, M5G 1L7, Canada
| | - Michael Ohh
- Department of Laboratory Medicine and Pathobiology, University of Toronto, 661 University Avenue, Toronto, ON, M5G 1M1, Canada. .,Department of Biochemistry, University of Toronto, 661 University Avenue, Toronto, ON, M5G 1M1, Canada.
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45
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Zhang F, Cao H. MicroRNA‑143‑3p suppresses cell growth and invasion in laryngeal squamous cell carcinoma via targeting the k‑Ras/Raf/MEK/ERK signaling pathway. Int J Oncol 2018; 54:689-701. [PMID: 30535502 DOI: 10.3892/ijo.2018.4655] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2017] [Accepted: 07/02/2018] [Indexed: 11/06/2022] Open
Abstract
MicroRNAs (miRNAs or miRs) have been identified as an important regulator in carcinogenesis and other pathological processes. However, the molecular mechanism underlying the function of miRNAs in the progression and development of laryngeal squamous cell carcinoma (LSCC) remains to be fully elucidated. In the present study, the miRNA expression pattern in LSCC tissues was profiled using miRNA microarray analysis. It was found that a large set of miRNAs are aberrantly expressed in LSCC tissues and that miR‑143‑3p was the most markedly downregulated compared with normal tissues. The low expression of miR‑143‑3p was associated with poor prognosis in LSCC. The overexpression of miR‑143‑3p repressed cellular proliferation and induced apoptosis in vitro, and inhibited tumor growth in vivo. The upregulation of miR‑143‑3p suppressed cell migration and invasion through inhibiting the epithelial‑mesenchymal transition cascade. In addition, it was verified that the oncogene k‑Ras is a target of miR‑143‑3p in LSCC cells, and the suppressive effects of miR‑143‑3p on LSCC cells were abrogated by the overexpression of k‑Ras. It was also revealed that miR‑143‑3p may inhibit cell growth and metastasis through targeting the k‑Ras/Raf/mitogen‑activated protein kinase kinase (MEK)/extracellular signal‑regulated kinase (ERK) signaling pathway. Taken together, the data indicated that the miR‑143‑3p/k‑Ras/Raf/MEK/ERK axis serves a key regulator in the development and progression of LSCC, suggesting that miR‑143‑3p may be a potential prognostic biomarker and therapeutic target in the treatment of LSCC.
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Affiliation(s)
- Feng Zhang
- Ear Nose and Throat Hospital, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Hua Cao
- Ear Nose and Throat Hospital, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
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46
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Farzaei MH, Tewari D, Momtaz S, Argüelles S, Nabavi SM. Targeting ERK signaling pathway by polyphenols as novel therapeutic strategy for neurodegeneration. Food Chem Toxicol 2018; 120:183-195. [PMID: 29981370 DOI: 10.1016/j.fct.2018.07.010] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2018] [Revised: 06/23/2018] [Accepted: 07/04/2018] [Indexed: 12/12/2022]
Abstract
Numerous chemicals, such as phenolic compounds are strong radical scavengers, capable of alleviating oxidative stress induced neurodegeneration. Dietary antioxidants, especially flavonoids, are being considered as a promising approach to prevent or slow the pathological development of neurological illness and aging. One of the major advantage of natural products is that of their anti-amyloid effects over synthetic counterpart, however a healthy diet provides these beneficial natural substances as nutraceuticals. The extracellular-signal-regulated kinase (ERK) is one of the main pharmacological target of natural phenolic compounds, participating in several therapeutic effects. Mounting evidence revealed that numerous bioflavonoids, obtained from a variety of dietary fruits or plants as well as medicinal herbal sources, exhibit protective or therapeutic functions versus development of neurodegenerative diseases mainly through modulation of different compartments of ERK signaling pathway. Currently, there is remarkable interest in the beneficial effects of natural flavonoids to improve neural performance and prevent the onset and development of major neurodegenerative diseases. Natural products originated from medicinal plants, in particular antioxidants, have gained a great deal of attention due to their safe and non-toxic natures. Here, we summarized the effect of natural bioflavonoids on ERK signaling pathway and their molecular mechanism.
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Affiliation(s)
- Mohammad Hosein Farzaei
- Pharmaceutical Sciences Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran; Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran.
| | - Devesh Tewari
- Department of Pharmaceutical Sciences, Faculty of Technology, Bhimtal Campus, Kumaun University, Nainital, Uttarakhand, India
| | - Saeideh Momtaz
- Medicinal Plants Research Center, Institute of Medicinal Plants, ACECR, Karaj, Iran; Toxicology and Diseases Group, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | - Sandro Argüelles
- Department of Physiology, Faculty of Pharmacy, University of Seville, Seville, Spain
| | - Seyed Mohammad Nabavi
- Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran.
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47
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Design, synthesis, and biological evaluation of Cyclobentinib (CB1107) as a potential anti-CML agent. Med Chem Res 2018. [DOI: 10.1007/s00044-018-2198-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
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48
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Phillips MB, Stuart JD, Rodríguez Stewart RM, Berry JT, Mainou BA, Boehme KW. Current understanding of reovirus oncolysis mechanisms. Oncolytic Virother 2018; 7:53-63. [PMID: 29942799 PMCID: PMC6005300 DOI: 10.2147/ov.s143808] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Mammalian orthoreovirus (reovirus) is under development as a cancer virotherapy. Clinical trials demonstrate that reovirus-based therapies are safe and tolerated in patients with a wide variety of cancers. Although reovirus monotherapy has proven largely ineffective, reovirus sensitizes cancer cells to existing chemotherapeutic agents and radiation. Clinical trials are underway to test the efficacy of reovirus in combination with chemotherapeutic and radiation regimens and to evaluate the effectiveness of reovirus in conjunction with immunotherapies. Central to the use of reovirus to treat cancer is its capacity to directly kill cancer cells and alter the cellular environment to augment other therapies. Apoptotic cell death is a prominent mechanism of reovirus cancer cell killing. However, reoviruses can also kill cancer cells through nonapoptotic mechanisms. Here, we describe mechanisms of reovirus cancer cell killing, highlight how reovirus is used in combination with existing cancer treatments, and discuss what is known as to how reovirus modulates cancer immunotherapy.
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Affiliation(s)
- Matthew B Phillips
- Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Atlanta, GA, USA
| | - Johnasha D Stuart
- Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Atlanta, GA, USA
| | | | | | | | - Karl W Boehme
- Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Atlanta, GA, USA
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49
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Kumar R, Khandelwal N, Thachamvally R, Tripathi BN, Barua S, Kashyap SK, Maherchandani S, Kumar N. Role of MAPK/MNK1 signaling in virus replication. Virus Res 2018; 253:48-61. [PMID: 29864503 PMCID: PMC7114592 DOI: 10.1016/j.virusres.2018.05.028] [Citation(s) in RCA: 97] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2018] [Revised: 04/16/2018] [Accepted: 05/31/2018] [Indexed: 12/23/2022]
Abstract
Viruses are known to exploit cellular signaling pathways. MAPK is a major cell signaling pathway activated by diverse group of viruses. MNK1 regulates both cap-dependent and IRES-mediated mRNA translation. This review discuss the role of MAPK, particularly the role of MNK1 in virus replication. Viruses are obligate intracellular parasites; they heavily depend on the host cell machinery to effectively replicate and produce new progeny virus particles. Following viral infection, diverse cell signaling pathways are initiated by the cells, with the major goal of establishing an antiviral state. However, viruses have been shown to exploit cellular signaling pathways for their own effective replication. Genome-wide siRNA screens have also identified numerous host factors that either support (proviral) or inhibit (antiviral) virus replication. Some of the host factors might be dispensable for the host but may be critical for virus replication; therefore such cellular factors may serve as targets for development of antiviral therapeutics. Mitogen activated protein kinase (MAPK) is a major cell signaling pathway that is known to be activated by diverse group of viruses. MAPK interacting kinase 1 (MNK1) has been shown to regulate both cap-dependent and internal ribosomal entry sites (IRES)-mediated mRNA translation. In this review we have discuss the role of MAPK in virus replication, particularly the role of MNK1 in replication and translation of viral genome.
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Affiliation(s)
- Ram Kumar
- Virology Laboratory, National Centre for Veterinary Type Cultures, ICAR-National Research Centre on Equines, Hisar, Haryana 125001, India; Department of Veterinary Microbiology and Biotechnology, Rajasthan University of Veterinary and Animal Sciences, Bikaner, Rajasthan 334001, India
| | - Nitin Khandelwal
- Virology Laboratory, National Centre for Veterinary Type Cultures, ICAR-National Research Centre on Equines, Hisar, Haryana 125001, India
| | - Riyesh Thachamvally
- Virology Laboratory, National Centre for Veterinary Type Cultures, ICAR-National Research Centre on Equines, Hisar, Haryana 125001, India
| | - Bhupendra Nath Tripathi
- Virology Laboratory, National Centre for Veterinary Type Cultures, ICAR-National Research Centre on Equines, Hisar, Haryana 125001, India
| | - Sanjay Barua
- Virology Laboratory, National Centre for Veterinary Type Cultures, ICAR-National Research Centre on Equines, Hisar, Haryana 125001, India
| | - Sudhir Kumar Kashyap
- Department of Veterinary Microbiology and Biotechnology, Rajasthan University of Veterinary and Animal Sciences, Bikaner, Rajasthan 334001, India
| | - Sunil Maherchandani
- Department of Veterinary Microbiology and Biotechnology, Rajasthan University of Veterinary and Animal Sciences, Bikaner, Rajasthan 334001, India
| | - Naveen Kumar
- Virology Laboratory, National Centre for Veterinary Type Cultures, ICAR-National Research Centre on Equines, Hisar, Haryana 125001, India.
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50
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Schmidt ML, Hobbing KR, Donninger H, Clark GJ. RASSF1A Deficiency Enhances RAS-Driven Lung Tumorigenesis. Cancer Res 2018; 78:2614-2623. [PMID: 29735543 DOI: 10.1158/0008-5472.can-17-2466] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2017] [Revised: 01/26/2018] [Accepted: 03/01/2018] [Indexed: 12/30/2022]
Abstract
Mutant K-RAS has been shown to have both tumor-promoting and -suppressing functions, and growing evidence suggests that the RASSF family of tumor suppressors can act as RAS apoptosis and senescence effectors. It has been hypothesized that inactivation of the RASSF1A tumor suppressor facilitates K-RAS-mediated transformation by uncoupling it from apoptotic pathways such as the Hippo pathway. In human lung tumors, combined activation of K-RAS and inactivation of RASSF1A is closely associated with the development of the most aggressive and worst prognosis tumors. Here, we describe the first transgenic mouse model for activation of K-RAS in the lung in a RASSF1A-defective background. RASSF1A deficiency profoundly enhanced the development of K-RAS-driven lung tumors in vivo Analysis of these tumors showed loss of RASSF1A-uncoupled RAS from the proapoptotic Hippo pathway as expected. We also observed an upregulation of AKT and RALGEF signaling in the RASSF1A- tumors. Heterozygosity of RASSF1A alone mimicked many of the effects of RAS activation on mitogenic signaling in lung tissue, yet no tumors developed, indicating that nonstandard Ras signaling pathways may be playing a key role in tumor formation in vivo In addition, we observed a marked increase in inflammation and IL6 production in RASSF1A-deficient tumors. Thus, RASSF1A loss profoundly affects RAS-driven lung tumorigenesis and mitogenic signaling in vivo Deregulation of inflammatory pathways due to loss of RASSF1A may be essential for RAS-mediated tumorigenesis. These results may have considerable ramifications for future targeted therapy against RAS+/RASSF1A- tumors.Significance: A transgenic mouse model shows that suppression of RASSF1A dramatically enhances Ras-driven tumorigenesis and alters Ras signaling pathway activity.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/10/2614/F1.large.jpg Cancer Res; 78(10); 2614-23. ©2018 AACR.
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Affiliation(s)
- M Lee Schmidt
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky
| | - Katharine R Hobbing
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky
| | - Howard Donninger
- Department of Medicine, University of Louisville, Louisville, Kentucky
| | - Geoffrey J Clark
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky.
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