scholarly journals Structural basis for targeting human cancer antigen STEAP1 with antibodies

2020 ◽  
Author(s):  
Wout Oosterheert ◽  
Piet Gros
Keyword(s):  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Human Cancer ◽  
Reductase Activity ◽  
Integral Membrane Protein ◽  
Binding Domain ◽  
Structural Basis ◽  
Ferric Reductase ◽  
Reduction Of Iron ◽  
Promising Therapeutic Target

AbstractSix-transmembrane epithelial antigen of the prostate (STEAP1) is an integral membrane protein that is highly upregulated on the cell surface of several human cancers, making it a promising therapeutic target. It shares sequence homology with three enzymes (STEAP2-4) that catalyze the NADPH-dependent reduction of iron(III). However, STEAP1 lacks an intracellular NADPH-binding domain and does not exhibit cellular ferric-reductase activity. Thus, both the molecular function of STEAP1 and its role in cancer progression remain elusive. Here, we present a ~3.0 Å cryo-electron microscopy structure of trimeric human STEAP1 bound to three Fab-fragments of the clinically employed antibody mAb120.545. STEAP1 adopts a reductase-like conformation and interacts with the Fabs through its extracellular helices. Enzymatic assays in human cells reveal that STEAP1 promotes iron(III) reduction when fused to the intracellular NADPH-binding domain of its family member STEAP4, implicating STEAP1 as a functional ferric reductase in STEAP hetero-trimers. Our work provides a foundation for deciphering the molecular mechanisms of STEAP1 and will be instrumental in the design of new therapeutic strategies to target STEAP1 in cancer.

scholarly journals Cryo-electron microscopy structure and potential enzymatic function of human six-transmembrane epithelial antigen of the prostate 1 (STEAP1)

2020 ◽  
Vol 295 (28) ◽  
pp. 9502-9512 ◽  
Author(s):  
Wout Oosterheert ◽  
Piet Gros
Keyword(s):  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Reductase Activity ◽  
Integral Membrane Protein ◽  
Binding Domain ◽  
Ferric Reductase ◽  
Enzymatic Assays ◽  
Enzymatic Function ◽  
Reduction Of Iron ◽  
Promising Therapeutic Target

Six-transmembrane epithelial antigen of the prostate 1 (STEAP1) is an integral membrane protein that is highly up-regulated on the cell surface of several human cancers, making it a promising therapeutic target to manage these diseases. It shares sequence homology with three enzymes (STEAP2–STEAP4) that catalyze the NADPH-dependent reduction of iron(III). However, STEAP1 lacks an intracellular NADPH-binding domain and does not exhibit cellular ferric reductase activity. Thus, both the molecular function of STEAP1 and its role in cancer progression remain elusive. Here, we present a ∼3.0-Å cryo-EM structure of trimeric human STEAP1 bound to three antigen-binding fragments (Fabs) of the clinically used antibody mAb120.545. The structure revealed that STEAP1 adopts a reductase-like conformation and interacts with the Fabs through its extracellular helices. Enzymatic assays in human cells revealed that STEAP1 promotes iron(III) reduction when fused to the intracellular NADPH-binding domain of its family member STEAP4, suggesting that STEAP1 functions as a ferric reductase in STEAP heterotrimers. Our work provides a foundation for deciphering the molecular mechanisms of STEAP1 and may be useful in the design of new therapeutic strategies to target STEAP1 in cancer.

scholarly journals Riddle of the Sphinx: Emerging Role of Transfer RNAs in Human Cancer

2021 ◽  
Vol 12 ◽  
Author(s):  
Zhilin Qiu ◽  
Qin Wang ◽  
Lei Liu ◽  
Guozheng Li ◽  
Yi Hao ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Cancer Susceptibility ◽  
Current Knowledge ◽  
Human Cancer ◽  
Special Focus ◽  
Basic Characteristics ◽  
Knowledge Of Cancer ◽  
Cancer Diagnosis And Therapy

The dysregulation of transfer RNA (tRNA) expression contributes to the diversity of proteomics, heterogeneity of cell populations, and instability of the genome, which may be related to human cancer susceptibility. However, the relationship between tRNA dysregulation and cancer susceptibility remains elusive because the landscape of cancer-associated tRNAs has not been portrayed yet. Furthermore, the molecular mechanisms of tRNAs involved in tumorigenesis and cancer progression have not been systematically understood. In this review, we detail current knowledge of cancer-related tRNAs and comprehensively summarize the basic characteristics and functions of these tRNAs, with a special focus on their role and involvement in human cancer. This review bridges the gap between tRNAs and cancer and broadens our understanding of their relationship, thus providing new insights and strategies to improve the potential clinical applications of tRNAs for cancer diagnosis and therapy.

scholarly journals The emerging role of SPOP protein in tumorigenesis and cancer therapy

2020 ◽  
Vol 19 (1) ◽  
Author(s):  
Yizuo Song ◽  
Yichi Xu ◽  
Chunyu Pan ◽  
Linzhi Yan ◽  
Zhi-wei Wang ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Human Cancer ◽  
Critical Role ◽  
Cancer Type ◽  
Nuclear Speckle ◽  
Ring E3 Ligase ◽  
Promising Therapeutic Target ◽  
Liver Cancers ◽  
Ring E3

AbstractThe nuclear speckle-type pox virus and zinc finger (POZ) protein (SPOP), a representative substrate-recognition subunit of the cullin-RING E3 ligase, has been characterized to play a dual role in tumorigenesis and cancer progression. Numerous studies have determined that SPOP suppresses tumorigenesis in a variety of human malignancies such as prostate, lung, colon, gastric, and liver cancers. However, several studies revealed that SPOP exhibited oncogenic function in kidney cancer, suggesting that SPOP could exert its biological function in a cancer type-specific manner. The role of SPOP in thyroid, cervical, ovarian, bone and neurologic cancers has yet to be determined. In this review article, we describe the structure and regulation of SPOP in human cancer. Moreover, we highlight the critical role of SPOP in tumorigenesis based on three major categories: physiological evidence (animal models), pathological evidence (human cancer specimens) and biochemical evidence (downstream ubiquitin substrates). Furthermore, we note that SPOP could be a promising therapeutic target for cancer treatment.

scholarly journals The Cancer Microbiota: EMT and Inflammation as Shared Molecular Mechanisms Associated with Plasticity and Progression

2019 ◽  
Vol 2019 ◽  
pp. 1-16 ◽  
Author(s):  
Daniele Vergara ◽  
Pasquale Simeone ◽  
Marina Damato ◽  
Michele Maffia ◽  
Paola Lanuti ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Common Ground ◽  
Epithelial Mesenchymal Transition ◽  
Human Cancer ◽  
Malignant Progression ◽  
Pathogenic Microorganisms ◽  
Mesenchymal Transition ◽  
Host Interactions

With the advent of novel molecular platforms for high-throughput/next-generation sequencing, the communities of commensal and pathogenic microorganisms that inhabit the human body have been defined in depth. In the last decade, the role of microbiota-host interactions in driving human cancer plasticity and malignant progression has been well documented. Germ-free preclinical models provided an invaluable tool to demonstrate that the human microbiota can confer susceptibility to various types of cancer and can also modulate the host response to therapeutic treatments. Of interest, besides the detrimental effects of dysbiosis on cancer etiopathogenesis, specific microorganisms have been shown to exert protective activities against cancer growth. This has strong clinical implications, as restoration of the physiologic microbiota is being rapidly implemented as a novel anticancer therapeutic strategy. Here, we reviewed past and recent literature depicting the role of microbiota-host interactions in modulating key molecular mechanisms that drive human cancer plasticity and lead to malignant progression. We analyzed microbiota-host interactions occurring in the gut as well as in other anatomic sites, such as oral and nasal cavities, lungs, breast, esophagus, stomach, reproductive tract, and skin. We revealed a common ground of biological alterations and pathways modulated by a dysbiotic microbiota and potentially involved in the control of cancer progression. The molecular mechanisms most frequently affected by the pathogenic microorganisms to induce malignant progression involve epithelial-mesenchymal transition- (EMT-) dependent barrier alterations and tumor-promoting inflammation. This evidence may pave the way to better stratify high-risk cancer patients based on unique microenvironmental/microbial signatures and to develop novel, personalized, biological therapies.

scholarly journals Multifunctional Roles of miR-34a in Cancer: A Review with the Emphasis on Head and Neck Squamous Cell Carcinoma and Thyroid Cancer with Clinical Implications

Diagnostics ◽  
2020 ◽  
Vol 10 (8) ◽  
pp. 563
Author(s):  
David Kalfert ◽  
Marie Ludvikova ◽  
Martin Pesta ◽  
Jaroslav Ludvik ◽  
Lucie Dostalova ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Head And Neck ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Current Knowledge ◽  
Human Cancer ◽  
Squamous Carcinoma ◽  
Transcriptional Level ◽  
Mesenchymal Transition

MiR-34a belongs to the class of small non-coding regulatory RNAs and functions as a tumor suppressor. Under physiological conditions, miR-34a has an inhibitory effect on all processes related to cell proliferation by targeting many proto-oncogenes and silencing them on the post-transcriptional level. However, deregulation of miR-34a was shown to play important roles in tumorigenesis and processes associated with cancer progression, such as tumor-associated epithelial-mesenchymal transition, invasion, and metastasis. Moreover, further understanding of miR-34a molecular mechanisms in cancer are indispensable for the development of effective diagnosis and treatments. In this review, we summarized the current knowledge on miR-34a functions in human disease with an emphasis on its regulation and dysregulation, its role in human cancer, specifically head and neck squamous carcinoma and thyroid cancer, and emerging role as a disease diagnostic and prognostic biomarker and the novel therapeutic target in oncology.

scholarly journals Combined Systematic Review and Transcriptomic Analyses of Mammalian Aquaporin Classes 1 to 10 as Biomarkers and Prognostic Indicators in Diverse Cancers

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1911 ◽  
Author(s):  
Pak Hin Chow ◽  
Joanne Bowen ◽  
Andrea J Yool
Keyword(s):  
Systematic Review ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Human Cancer ◽  
Survival Rates ◽  
Prognostic Indicators ◽  
Breast Cancers ◽  
Survival Times ◽  
Fluid Homeostasis ◽  
Risk Of Death

Aquaporin (AQP) channels enable regulated transport of water and solutes essential for fluid homeostasis, but they are gaining attention as targets for anticancer therapies. Patterns of AQP expression and survival rates for patients were evaluated by systematic review (PubMed and Embase) and transcriptomic analyses of RNAseq data (Human Protein Atlas database). Meta-analyses confirmed predominantly negative associations between AQP protein and RNA expression levels and patient survival times, most notably for AQP1 in lung, breast and prostate cancers; AQP3 in esophageal, liver and breast cancers; and AQP9 in liver cancer. Patterns of AQP expression were clustered for groups of cancers and associated with risk of death. A quantitative transcriptomic analysis of AQP1-10 in human cancer biopsies similarly showed that increased transcript levels of AQPs 1, 3, 5 and 9 were most frequently associated with poor survival. Unexpectedly, increased AQP7 and AQP8 levels were associated with better survival times in glioma, ovarian and endometrial cancers, and increased AQP11 with better survival in colorectal and breast cancers. Although molecular mechanisms of aquaporins in pathology or protection remain to be fully defined, results here support the hypothesis that overexpression of selected classes of AQPs differentially augments cancer progression. Beyond fluid homeostasis, potential roles for AQPs in cancers (suggested from an expanding appreciation of their functions in normal tissues) include cell motility, membrane process extension, transport of signaling molecules, control of proliferation and apoptosis, increased mechanical compliance, and gas exchange. AQP expression also has been linked to differences in sensitivity to chemotherapy treatments, suggesting possible roles as biomarkers for personalized treatments. Development of AQP pharmacological modulators, administered in cancer-specific combinations, might inspire new interventions for controlling malignant carcinomas.

scholarly journals The Dual Role of TGFβ in Human Cancer: From Tumor Suppression to Cancer Metastasis

2012 ◽  
Vol 2012 ◽  
pp. 1-28 ◽  
Author(s):  
Jean-Charles Neel ◽  
Laure Humbert ◽  
Jean-Jacques Lebrun
Keyword(s):  
Cell Growth ◽  
Cancer Progression ◽  
Transforming Growth Factor Beta ◽  
Molecular Mechanisms ◽  
Cancer Metastasis ◽  
Transforming Growth Factor ◽  
Human Cancer ◽  
Adult Life ◽  
Dual Role

The transforming growth factor-beta (TGFβ) superfamily encompasses widespread and evolutionarily conserved polypeptide growth factors that regulate and orchestrate growth and differentiation in all cell types and tissues. While they regulate asymmetric cell division and cell fate determination during early development and embryogenesis, TGFβ family members play a major regulatory role in hormonal and immune responses, cell growth, cell death and cell immortalization, bone formation, tissue remodeling and repair, and erythropoiesis throughout adult life. The biological and physiological functions of TGFβ, the founding member of this family, and its receptors are of central importance to human diseases, particularly cancer. By regulating cell growth, death, and immortalization, TGFβ signaling pathways exert tumor suppressor effects in normal cells and early carcinomas. Thus, it is not surprising that a high number of human tumors arise due to mutations or deletions in the genes coding for the various TGFβ signaling components. As tumors develop and progress, these protective and cytostatic effects of TGFβ are often lost. TGFβ signaling then switches to promote cancer progression, invasion, and tumor metastasis. The molecular mechanisms underlying this dual role of TGFβ in human cancer will be discussed in depth in this paper, and it will highlight the challenge and importance of developing novel therapeutic strategies specifically aimed at blocking the prometastatic arm of the TGFβ signaling pathway without affecting its tumor suppressive effects.

WORKSHOP ABSTRACTS

2006 ◽  
Vol 10 (13) ◽  
pp. 88-155
Keyword(s):  
Cancer Progression ◽  
Cell Biology ◽  
Molecular Mechanisms ◽  
Viral Infections ◽  
Academic Career ◽  
Human Cancer ◽  
Genetic Diseases ◽  
Genomic Medicine ◽  
Genetic Changes ◽  
Antiviral Therapies

SCBA Special WORKSHOP #1 NIH WORKSHOP NIH — Goes Electronic: How to Get Grants In the E-age? SCBA Special WORKSHOP #2 ACGA WORKSHOP — Genetic Diseases and Genomic Medicine. SCBA Special WORKSHOP #3 Genetic Changes and Mechanisms Contributing to Human Cancer. SCBA Special WORKSHOP #4 Upward Mobility in the Industrial and Academic Career. SCBA WORKSHOP #1: RNA Interference. SCBA WORKSHOP #2: Vaccine and Antiviral Therapies. SCBA WORKSHOP #3: Regulation and Modification of p53. SCBA WORKSHOP #4: Opioid Receptors: Molecules, Cells and the Whole Animal. SCBA WORKSHOP #5: Nuclear Receptor. SCBA WORKSHOP #6: Immune Responses and Signaling. SCBA WORKSHOP #7: Frontiers in Gene Therapy. SCBA WORKSHOP #8: Pathogenesis and Treatments of Neurophsychiatric and Neurodegenerative Diseases: New Understandings and New Possibilities. SCBA WORKSHOP #9: Nanotechnologies and Microfluidics for Biotech Application. SCBA WORKSHOP #10: Basic Mechanisms of Ubiquitination, NEDDDylation ISG-15 Modification. SCBA WORKSHOP #11: Neuronal Signaling and Synaptic Plasticity. SCBA WORKSHOP #12: Signal Transduction 1. SCBA WORKSHOP #13: Chemical Genetics. SCBA WORKSHOP #14: Plant Science and Epigenics Biology. SCBA WORKSHOP #15: Cytokines and Inflammation. SCBA WORKSHOP #16: Novel Post-Translation Modifications. SCBA WORKSHOP #17: Translational Medicine. SCBA WORKSHOP #18: Acetylationa in Ubiquitinatio in Chromatin-Templated Processes. SCBA WORKSHOP #19: Pathogenesis of Viral Infections. SCBA WORKSHOP #20: Stem Cell Biology and Regenerative Medicine. SCBA WORKSHOP #21: Biotech Panel: The making of a Successful Biotech Company. SCBA WORKSHOP #22: Molecular Mechanisms of Cancer Progression and Therapeutic Resistance. SCBA WORKSHOP #23: Regulatory Geneomics and Epigenomics. SCBA WORKSHOP #24: RNA Biology. SCBA WORKSHOP #25: Bioprocessing. SCBA WORKSHOP #26: Recent Development of Targeted Therapy. SCBA WORKSHOP #27: DNA Damage Response in Eukaryotes. SCBA WORKSHOP #28: The Biology and Promise of Neural Stem Cells. SCBA WORKSHOP #29: IP and Business Licensing. SCBA WORKSHOP #30: Basic Mechanisms of Sumoylation. SCBA WORKSHOP #31: Immune Regulation and Therapy. SCBA WORKSHOP #32: Proteomics and Applications.

Design, Synthesis, and Preliminary Bioactivity Evaluation of 2,7-Substituted Carbazole Derivatives as Potent Autotaxin Inhibitors and Antitumor Agents†

2019 ◽  
Vol 19 (2) ◽  
pp. 256-264
Author(s):  
Wenming Wang ◽  
Fengmei Zhao ◽  
Yarui Zhao ◽  
Weiwei Pan ◽  
Pengcheng Cao ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Enzymatic Activity ◽  
Cancer Progression ◽  
Anticancer Agents ◽  
Antitumor Agents ◽  
Hydrophobic Interactions ◽  
Human Cancer ◽  
Structural Basis ◽  
Human Carcinoma ◽  
Carbazole Derivatives

Background: Autotaxin-LPA signaling has been implicated in cancer progression, and targeted for the discovery of cancer therapeutic agents. Objective: Potential ATX inhibitors were synthesized to develop novel leading compounds and effective anticancer agents. Methods: The present work designs and synthesizes a series of 2,7-subsitituted carbazole derivatives with different terminal groups R [R = -Cl (I), -COOH (II), -B(OH)2 (III), or -PO(OH)2 (I-IV)]. The inhibition of these compounds on the enzymatic activity of ATX was measured using FS-3 and Bis-pNpp as substrates, and the cytotoxicity of these compounds was evaluated using SW620, SW480, PANC-1, and SKOV-3 human carcinoma cells. Furthermore, the binding of leading compound with ATX was analyzed by molecular docking. Results: Compound III was shown to be a promising antitumor candidate by demonstrating both good inhibition of ATX enzymatic activity and high cytotoxicity against human cancer cell lines. Molecular docking study shows that compound III is located in a pocket, which mainly comprises amino acids 209 to 316 in domain 2 of ATX, and binds with these residues of ATX through van der Waals, conventional hydrogen bonds, and hydrophobic interactions. Conclusion: Compound III with the terminal group R = -B(OH)2 has the most potent inhibitory effect with the greatest cytotoxicity to cancer cells. Moreover, the docking model provides a structural basis for the future optimization of promising antitumor compounds.

scholarly journals MicroRNA-744 Inhibits Cellular Proliferation and Invasion of Colorectal Cancer by Directly Targeting Oncogene Notch1

2018 ◽  
Vol 26 (9) ◽  
pp. 1401-1409 ◽  
Author(s):  
Jian Shen ◽  
Minzhe Li
Keyword(s):  
Colorectal Cancer ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Cellular Proliferation ◽  
Human Cancer ◽  
Inhibitory Effects ◽  
Direct Target ◽  
Future Treatments ◽  
Proliferation And Invasion ◽  
Comprehensive Study

Accumulated studies have strongly implicated aberrantly expressed microRNAs (miRNAs) in carcinogenesis and cancer progression of various cancers, including colorectal cancer (CRC). Hence, a comprehensive study of miRNAs and their association with CRC may be a promising therapeutic method for patients with this malignancy. MicroRNA-744 (miR-744) is abnormally expressed in several types of human cancer. Thus far, little is known about the expression, biological roles, and exact mechanisms of miR-744 in CRC. Thus, the present study measured the expression level of miR-744 and investigated its roles and associated molecular mechanisms in CRC. This study demonstrated that miR-744 expression was significantly underexpressed in CRC tissues and cell lines. Low miR-744 expression was positively associated with lymphatic metastasis and TNM stage. Functional experiments revealed that miR-744 overexpression obviously inhibited the proliferation and invasion of CRC cells. Furthermore, Notch1 was identified as a direct target of miR-744 in CRC. Moreover, the inhibition of Notch1 phenocopied the inhibitory effects of miR-744 overexpression on CRC cells. Restored Notch1 expression markedly rescued the tumor-suppressive effects of miR-744 overexpression on CRC cells. Overall, miR-744 exhibits an essential role in CRC progression, and the miR-744/Notch1 axis may provide novel insights into future treatments for patients with CRC.

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