scholarly journals Cancer chemoprevention through Frizzled receptors and EMT

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
K. Sompel ◽  
A. Elango ◽  
A. J. Smith ◽  
M. A. Tennis
Keyword(s):  
Small Molecules ◽  
Epithelial To Mesenchymal Transition ◽  
Cancer Chemoprevention ◽  
Premalignant Lesions ◽  
Transmembrane Receptors ◽  
Mesenchymal Transition ◽  
Chemopreventive Agent ◽  
Wide Range ◽  
Canonical Pathways ◽  
Frizzled Receptors

AbstractFrizzled (FZD) transmembrane receptors are well known for their role in β-catenin signaling and development and now understanding of their role in the context of cancer is growing. FZDs are often associated with the process of epithelial to mesenchymal transition (EMT) through β-catenin, but some also influence EMT through non-canonical pathways. With ten different FZDs, there is a wide range of activity from oncogenic to tumor suppressive depending on the tissue context. Alterations in FZD signaling can occur during development of premalignant lesions, supporting their potential as targets of chemoprevention agents. Agonizing or antagonizing FZD activity may affect EMT, which is a key process in lesion progression often targeted by chemoprevention agents. Recent studies identified a specific FZD as important for activity of an EMT inhibiting chemopreventive agent and other studies have highlighted the previously unrecognized potential for targeting small molecules to FZD receptors. This work demonstrates the value of investigating FZDs in chemoprevention and here we provide a review of FZDs in cancer EMT and their potential as chemoprevention targets.

scholarly journals Proteomic Analysis of Zeb1 Interactome in Breast Carcinoma Cells

Molecules ◽  
2021 ◽  
Vol 26 (11) ◽  
pp. 3143
Author(s):  
Sergey E. Parfenyev ◽  
Sergey V. Shabelnikov ◽  
Danila Y. Pozdnyakov ◽  
Olga O. Gnedina ◽  
Leonid S. Adonin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Critical Role ◽  
Malignant Neoplasm ◽  
Malignant Neoplasms ◽  
Breast Cancer Patients ◽  
Survival Prognosis ◽  
Mesenchymal Transition ◽  
Wide Range

Breast cancer is the most frequently diagnosed malignant neoplasm and the second leading cause of cancer death among women. Epithelial-to-mesenchymal Transition (EMT) plays a critical role in the organism development, providing cell migration and tissue formation. However, its erroneous activation in malignancies can serve as the basis for the dissemination of cancer cells and metastasis. The Zeb1 transcription factor, which regulates the EMT activation, has been shown to play an essential role in malignant transformation. This factor is involved in many signaling pathways that influence a wide range of cellular functions via interacting with many proteins that affect its transcriptional functions. Importantly, the interactome of Zeb1 depends on the cellular context. Here, using the inducible expression of Zeb1 in epithelial breast cancer cells, we identified a substantial list of novel potential Zeb1 interaction partners, including proteins involved in the formation of malignant neoplasms, such as ATP-dependent RNA helicase DDX17and a component of the NURD repressor complex, CTBP2. We confirmed the presence of the selected interactors by immunoblotting with specific antibodies. Further, we demonstrated that co-expression of Zeb1 and CTBP2 in breast cancer patients correlated with the poor survival prognosis, thus signifying the functionality of the Zeb1–CTBP2 interaction.

scholarly journals Growth Hormone Upregulates Mediators of Melanoma Drug Efflux and Epithelial-to-Mesenchymal Transition In Vitro and In Vivo

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3640
Author(s):  
Yanrong Qian ◽  
Reetobrata Basu ◽  
Samuel C. Mathes ◽  
Nathan A. Arnett ◽  
Silvana Duran-Ortiz ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Epithelial To Mesenchymal Transition ◽  
Human Melanoma ◽  
Drug Efflux ◽  
Mesenchymal Transition ◽  
Mouse Melanoma ◽  
Wide Range ◽  
Mouse Lines

Growth hormone (GH) and the GH receptor (GHR) are expressed in a wide range of malignant tumors including melanoma. However, the effect of GH/insulin-like growth factor (IGF) on melanoma in vivo has not yet been elucidated. Here we assessed the physical and molecular effects of GH on mouse melanoma B16-F10 and human melanoma SK-MEL-30 cells in vitro. We then corroborated these observations with syngeneic B16-F10 tumors in two mouse lines with different levels of GH/IGF: bovine GH transgenic mice (bGH; high GH, high IGF-1) and GHR gene-disrupted or knockout mice (GHRKO; high GH, low IGF-1). In vitro, GH treatment enhanced mouse and human melanoma cell growth, drug retention and cell invasion. While the in vivo tumor size was unaffected in both bGH and GHRKO mouse lines, multiple drug-efflux pumps were up regulated. This intrinsic capacity of therapy resistance appears to be GH dependent. Additionally, epithelial-to-mesenchymal transition (EMT) gene transcription markers were significantly upregulated in vivo supporting our current and recent in vitro observations. These syngeneic mouse melanoma models of differential GH/IGF action can be valuable tools in screening for therapeutic options where lowering GH/IGF-1 action is important.

scholarly journals Diverse properties of the mesothelial cells in health and disease

2016 ◽  
Vol 1 (2) ◽  
pp. 79-89 ◽  
Author(s):  
Kunio Kawanishi
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Fluid Transport ◽  
Reproductive Organs ◽  
Mesothelial Cells ◽  
The Body ◽  
Oxygen Species ◽  
Mesenchymal Transition ◽  
Wide Range ◽  
Health And Disease ◽  
Visceral Adipose

AbstractMesothelial cells (MCs) form the superficial anatomic layer of serosal membranes, including pleura, pericardium, peritoneum, and the tunica of the reproductive organs. MCs produce a protective, non-adhesive barrier against physical and biochemical damages. MCs express a wide range of phenotypic markers, including vimentin and cytokeratins. MCs play key roles in fluid transport and inflammation, as reflected by the modulation of biochemical markers such as transporters, adhesion molecules, cytokines, growth factors, reactive oxygen species and their scavengers. MCs synthesize extracellular matrix related molecules, and the surface of MC microvilli secretes a highly hydrophilic protective barrier, “glycocalyx”, consisting mainly of glycosaminoglycans. MCs maintain a balance between procoagulant and fibrinolytic activation by producing a whole range of regulators, can synthetize fibrin and therefore form adhesions. Synthesis and recognition of hyaluronan and sialic acids might be a new insight to explain immunoactive and immunoregulatory properties of MCs. Epithelial to mesenchymal transition of MCs may involve serosal repair and remodeling. MCs might also play a role in the development and remodeling of visceral adipose tissue. Taken together, MCs play important roles in health and disease in serosal cavities of the body. The mesothelium is not just a membrane and should be considered as an organ.

scholarly journals Metabolite sensing and signaling in cancer

2020 ◽  
Vol 295 (33) ◽  
pp. 11938-11946 ◽  
Author(s):  
Yi-Ping Wang ◽  
Jin-Tao Li ◽  
Jia Qu ◽  
Miao Yin ◽  
Qun-Ying Lei
Keyword(s):  
Cancer Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Cell Metabolism ◽  
Therapeutic Interventions ◽  
Metabolic Dysfunction ◽  
Mesenchymal Transition ◽  
Metabolic Intermediates ◽  
Cellular Processes ◽  
Signaling Function ◽  
Wide Range

Metabolites are not only substrates in metabolic reactions, but also signaling molecules controlling a wide range of cellular processes. Discovery of the oncometabolite 2-hydroxyglutarate provides an important link between metabolic dysfunction and cancer, unveiling the signaling function of metabolites in regulating epigenetic and epitranscriptomic modifications, genome integrity, and signal transduction. It is now known that cancer cells remodel their metabolic network to support biogenesis, caused by or resulting in the dysregulation of various metabolites. Cancer cells can sense alterations in metabolic intermediates to better coordinate multiple biological processes and enhance cell metabolism. Recent studies have demonstrated that metabolite signaling is involved in the regulation of malignant transformation, cell proliferation, epithelial-to-mesenchymal transition, differentiation blockade, and cancer stemness. Additionally, intercellular metabolite signaling modulates inflammatory response and immunosurveillance in the tumor microenvironment. Here, we review recent advances in cancer-associated metabolite signaling. An in depth understanding of metabolite signaling will provide new opportunities for the development of therapeutic interventions that target cancer.

Recent insights into the role of Notch signaling in tumorigenesis

Blood ◽  
2006 ◽  
Vol 107 (6) ◽  
pp. 2223-2233 ◽  
Author(s):  
Kevin G. Leong ◽  
Aly Karsan
Keyword(s):  
Notch Signaling ◽  
Cell Fate ◽  
Epithelial To Mesenchymal Transition ◽  
Cellular Functions ◽  
Cellular Mechanisms ◽  
Transmembrane Receptors ◽  
Mesenchymal Transition ◽  
Functional Aspects ◽  
Solid Malignancies

AbstractMembers of the Notch family of transmembrane receptors play an important role in cell fate determination. Over the past decade, a role for Notch in the pathogenesis of hematologic and solid malignancies has become apparent. Numerous cellular functions and microenvironmental cues associated with tumorigenesis are modulated by Notch signaling, including proliferation, apoptosis, adhesion, epithelial-to-mesenchymal transition, and angiogenesis. It is becoming increasingly evident that Notch signaling can be both oncogenic and tumor suppressive. This review highlights recent findings regarding the molecular and functional aspects of Notch-mediated neoplastic transformation. In addition, cellular mechanisms that potentially explain the complex role of Notch in tumorigenesis are discussed.

The role of DUBs in the post-translational control of cell migration

2019 ◽  
Vol 63 (5) ◽  
pp. 579-594 ◽  
Author(s):  
Guillem Lambies ◽  
Antonio García de Herreros ◽  
Víctor M. Díaz
Keyword(s):  
Cell Migration ◽  
Translational Control ◽  
Epithelial To Mesenchymal Transition ◽  
Extracellular Matrix Remodeling ◽  
Matrix Remodeling ◽  
Mesenchymal Transition ◽  
Tgfβ Receptors ◽  
Fundamental Process ◽  
Multistep Process

Abstract Cell migration is a multifactorial/multistep process that requires the concerted action of growth and transcriptional factors, motor proteins, extracellular matrix remodeling and proteases. In this review, we focus on the role of transcription factors modulating Epithelial-to-Mesenchymal Transition (EMT-TFs), a fundamental process supporting both physiological and pathological cell migration. These EMT-TFs (Snail1/2, Twist1/2 and Zeb1/2) are labile proteins which should be stabilized to initiate EMT and provide full migratory and invasive properties. We present here a family of enzymes, the deubiquitinases (DUBs) which have a crucial role in counteracting polyubiquitination and proteasomal degradation of EMT-TFs after their induction by TGFβ, inflammatory cytokines and hypoxia. We also describe the DUBs promoting the stabilization of Smads, TGFβ receptors and other key proteins involved in transduction pathways controlling EMT.

Understanding Conformational Entropy in Small Molecules

2020 ◽  
Author(s):  
Lucian Chan ◽  
Garrett Morris ◽  
Geoffrey Hutchison
Keyword(s):  
Small Molecules ◽  
Degrees Of Freedom ◽  
Absolute Error ◽  
Low Energy ◽  
Standard Entropy ◽  
Free Energies ◽  
Conformational Entropy ◽  
Wide Range ◽  
High Degree ◽  
Empirical Corrections

The calculation of the entropy of flexible molecules can be challenging, since the number of possible conformers grows exponentially with molecule size and many low-energy conformers may be thermally accessible. Different methods have been proposed to approximate the contribution of conformational entropy to the molecular standard entropy, including performing thermochemistry calculations with all possible stable conformations, and developing empirical corrections from experimental data. We have performed conformer sampling on over 120,000 small molecules generating some 12 million conformers, to develop models to predict conformational entropy across a wide range of molecules. Using insight into the nature of conformational disorder, our cross-validated physically-motivated statistical model can outperform common machine learning and deep learning methods, with a mean absolute error ≈4.8 J/mol•K, or under 0.4 kcal/mol at 300 K. Beyond predicting molecular entropies and free energies, the model implies a high degree of correlation between torsions in most molecules, often as- sumed to be independent. While individual dihedral rotations may have low energetic barriers, the shape and chemical functionality of most molecules necessarily correlate their torsional degrees of freedom, and hence restrict the number of low-energy conformations immensely. Our simple models capture these correlations, and advance our understanding of small molecule conformational entropy.

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