scholarly journals HMGA1, Moonlighting Protein Function, and Cellular Real Estate: Location, Location, Location!

Biomolecules ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 1334
Author(s):  
Mireia Pujals ◽  
Linda Resar ◽  
Josep Villanueva
Keyword(s):  
Cell Lines ◽  
Protein Function ◽  
Therapeutic Potential ◽  
Tumor Development ◽  
High Mobility ◽  
Extracellular Proteins ◽  
Metastatic Progression ◽  
Autocrine Loop ◽  
Tnbc Cell ◽  
Moonlighting Protein

The gene encoding the High Mobility Group A1 (HMGA1) chromatin remodeling protein is upregulated in diverse cancers where high levels portend adverse clinical outcomes. Until recently, HMGA1 was assumed to be a nuclear protein exerting its role in cancer by transcriptionally modulating gene expression and downstream signaling pathways. However, the discovery of an extracellular HMGA1-RAGE autocrine loop in invasive triple-negative breast cancer (TNBC) cell lines implicates HMGA1 as a “moonlighting protein” with different functions depending upon cellular location. Here, we review the role of HMGA1, not only as a chromatin regulator in cancer and stem cells, but also as a potential secreted factor that drives tumor progression. Prior work found that HMGA1 is secreted from TNBC cell lines where it signals through the receptor for advanced glycation end products (RAGE) to foster phenotypes involved in tumor invasion and metastatic progression. Studies in primary TNBC tumors also suggest that HMGA1 secretion associates with distant metastasis in TNBC. Given the therapeutic potential to target extracellular proteins, further work to confirm this role in other contexts is warranted. Indeed, crosstalk between nuclear and secreted HMGA1 could change our understanding of tumor development and reveal novel therapeutic opportunities relevant to diverse human cancers overexpressing HMGA1.

Targeting EZH2 in acral lentiginous melanoma (ALM).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 9534-9534 ◽  
Author(s):  
Allison Izsak ◽  
Keith Michael Giles ◽  
Kevin Paul Lui ◽  
Sarah A. Weiss ◽  
Una Moran ◽  
...  
Keyword(s):  
Cell Lines ◽  
Colony Formation ◽  
Therapeutic Potential ◽  
Histone Methyltransferase ◽  
Metastatic Progression ◽  
Primary Tumors ◽  
Acral Lentiginous Melanoma ◽  
Ezh2 Expression ◽  
Selective Sensitivity ◽  
In Transit

9534 Background: Efforts to identify targeted therapies that can improve treatment outcome in metastatic ALM have been unsuccessful. In a previous genomic screening, we identified copy number amplification of the histone methyltransferase EZH2 in 47% of ALM cases, a higher frequency than previously reported in cutaneous melanomas (CM) (5%). Here, we tested the hypothesis that increased EZH2 expression contributes to ALM progression and may confer selective sensitivity to EZH2 inhibition. Methods: EZH2 expression was examined by immunohistochemistry (IHC) in 51 primary (21 stage I, 13 Stage II and 17 Stage III) and 23 metastatic (11 in transit, 8 nodal and 4 visceral) ALM cases with extensive clinicopathological data and protocol-driven follow up. Colony formation and cell proliferation was assessed following treatment of ALM and CM cell lines with three EZH2 inhibitors, including GSK126, currently in clinical trials. The effect of GSK126 on H3K27me3 and downstream EZH2 targets was analyzed by western blotting. Results: EZH2 is commonly overexpressed in both primary (30/51; 65%) and metastatic (20/23; 87%) ALM cases, with a significant increase in mean IHC score between primary and metastatic tumors (1.9 vs. 2.7, respectively, p = 0.047). EZH2 expression increased in 6/10 metastatic ALM tumors compared to their matched primary tumors. ALM tumors with EZH2 gene amplification showed increased EZH2 protein expression; however more cases showed overexpression with no amplification suggesting a potential epigenetic component of EZH2 regulation. GSK126 significantly suppressed ALM colony formation at lower doses compared to CM (1 µM vs. 5 µM, respectively). EZH2 inhibition also increased expression of the downstream tumor suppressor E-cadherin in ALM but not in CM cell lines. Finally, ALM cell lines had significantly lower basal H3K27me3 levels than CM cell lines, suggesting an additional, histone methyltransferase-independent function of EZH2 in ALM. Conclusions: Our data demonstrate thatEZH2 upregulation is common in ALM, and suggest that it may play a role in ALM’s metastatic progression that requires further investigation. Selective sensitivity of ALM cell lines to EZH2 inhibitors supports the therapeutic potential of EZH2-targeted therapy in ALM.

High Mobility Group Box-1 (HMGB1): A Potential Target in Therapeutics

2019 ◽  
Vol 20 (14) ◽  
pp. 1474-1485 ◽  
Author(s):  
Eyaldeva C. Vijayakumar ◽  
Lokesh Kumar Bhatt ◽  
Kedar S. Prabhavalkar
Keyword(s):  
Myocardial Infarction ◽  
Vagus Nerve Stimulation ◽  
Nuclear Protein ◽  
Therapeutic Potential ◽  
High Mobility ◽  
Dna Binding Protein ◽  
High Mobility Group ◽  
Eukaryotic Cells ◽  
Hmgb1 Protein

High mobility group box-1 (HMGB1) mainly belongs to the non-histone DNA-binding protein. It has been studied as a nuclear protein that is present in eukaryotic cells. From the HMG family, HMGB1 protein has been focused particularly for its pivotal role in several pathologies. HMGB-1 is considered as an essential facilitator in diseases such as sepsis, collagen disease, atherosclerosis, cancers, arthritis, acute lung injury, epilepsy, myocardial infarction, and local and systemic inflammation. Modulation of HMGB1 levels in the human body provides a way in the management of these diseases. Various strategies, such as HMGB1-receptor antagonists, inhibitors of its signalling pathway, antibodies, RNA inhibitors, vagus nerve stimulation etc. have been used to inhibit expression, release or activity of HMGB1. This review encompasses the role of HMGB1 in various pathologies and discusses its therapeutic potential in these pathologies.

scholarly journals Overexpression of SERPINA3 promotes tumor invasion and migration, epithelial-mesenchymal-transition in triple-negative breast cancer cells

Breast Cancer ◽  
2021 ◽  
Author(s):  
Yingzi Zhang ◽  
Jiao Tian ◽  
Chi Qu ◽  
Yang Peng ◽  
Jinwei Lei ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Cell Lines ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Epithelial Mesenchymal Transition ◽  
Cell Counting ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Tnbc Cell

Abstract Background Recent studies have indicated that serpin peptidase inhibitor, clade A, member 3 (SERPINA3) is a potential marker associated with tumor progression, which connoted that SERPINA3 is related to malignant phenotypes in cancer. However, the biological function of SERPINA3 in breast cancer (BC) remains unclear. Methods Bioinformatics data were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Immunohistochemical staining (IHC) was conducted to determine SERPINA3 expression. With strong aggressive abilities, triple-negative breast cancer (TNBC) cell lines (MDA-MB-231, BT549 and MDA-MB-436) were obtained to examine SERPINA3 expression and functions. Wound healing and Transwell assays were performed to measure cell migration and invasion. Cell Counting Kit-8 (CCK-8) assay was conducted to detect cell proliferation abilities and cell viabilities. Results SERPINA3 was upregulated in BC tissues. Functional assays suggested that overexpression of SERPINA3 significantly promoted cell proliferation, where migration and invasion of TNBC cells were accelerated. Knockdown of SERPINA3 had the opposite effects. These results causing by overexpression of SERPINA3 were also confirmed in non-TNBC cell lines. Overexpression of SERPINA3 remarkably enhanced the epithelial–mesenchymal transition (EMT) by upregulating the EMT markers and EZH2. In addition, the overexpression of SERPINA3 reduced the sensitivity of TNBC cells to cisplatin. Conclusion SERPINA3 can regulate the migration, invasion and EMT of TNBC cells and increased expression of SERPINA3 confers resistance to cisplatin in TNBC cells. We discern it is required for the regulation of BC progression and is a critical target for the clinical treatment of BC.

scholarly journals Molecular and Pharmacological Characterization of the Interaction between Human Geranylgeranyltransferase Type I and Ras-Related Protein Rap1B

2021 ◽  
Vol 22 (5) ◽  
pp. 2501
Author(s):  
Sonja Hinz ◽  
Dominik Jung ◽  
Dorota Hauert ◽  
Hagen S. Bachmann
Keyword(s):  
Protein Function ◽  
Tumor Development ◽  
Cysteine Residue ◽  
Type I ◽  
Pharmacological Characterization ◽  
Anti Cancer ◽  
And Function ◽  
Caax Motif ◽  
Important Drug

Geranylgeranyltransferase type-I (GGTase-I) represents an important drug target since it contributes to the function of many proteins that are involved in tumor development and metastasis. This led to the development of GGTase-I inhibitors as anti-cancer drugs blocking the protein function and membrane association of e.g., Rap subfamilies that are involved in cell differentiation and cell growth. In the present study, we developed a new NanoBiT assay to monitor the interaction of human GGTase-I and its substrate Rap1B. Different Rap1B prenylation-deficient mutants (C181G, C181S, and ΔCQLL) were designed and investigated for their interaction with GGTase-I. While the Rap1B mutants C181G and C181S still exhibited interaction with human GGTase-I, mutant ΔCQLL, lacking the entire CAAX motif (defined by a cysteine residue, two aliphatic residues, and the C-terminal residue), showed reduced interaction. Moreover, a specific, peptidomimetic and competitive CAAX inhibitor was able to block the interaction of Rap1B with GGTase-I. Furthermore, activation of both Gαs-coupled human adenosine receptors, A2A (A2AAR) and A2B (A2BAR), increased the interaction between GGTase-I and Rap1B, probably representing a way to modulate prenylation and function of Rap1B. Thus, A2AAR and A2BAR antagonists might be promising candidates for therapeutic intervention for different types of cancer that overexpress Rap1B. Finally, the NanoBiT assay provides a tool to investigate the pharmacology of GGTase-I inhibitors.

scholarly journals Multiregional genetic evolution of metastatic uveal melanoma

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Daniel A. Rodriguez ◽  
Jessica Yang ◽  
Michael A. Durante ◽  
Alexander N. Shoushtari ◽  
Stergios J. Moschos ◽  
...  
Keyword(s):  
Uveal Melanoma ◽  
Tumor Development ◽  
Genetic Evolution ◽  
Metastatic Progression ◽  
Therapeutic Approaches ◽  
Primary Tumors ◽  
Early Tumor ◽  
Rapid Autopsy ◽  
Genetic Events ◽  
Novel Therapeutic

AbstractUveal melanoma (UM) is the most common primary intraocular malignancy in adults and leads to deadly metastases for which there is no approved treatment. Genetic events driving early tumor development are well-described, but those occurring later during metastatic progression remain poorly understood. We performed multiregional genomic sequencing on 22 tumors collected from two patients with widely metastatic UM who underwent rapid autopsy. We observed multiple seeding events from the primary tumors, metastasis-to-metastasis seeding, polyclonal seeding, and late driver variants in ATM, KRAS, and other genes previously unreported in UM. These findings reveal previously unrecognized temporal and anatomic complexity in the genetic evolution of metastatic uveal melanoma, and they highlight the distinction between early and late phases of UM genetic evolution with implications for novel therapeutic approaches.

scholarly journals Inhibition of the Myocardin-Related Transcription Factor Pathway Increases Efficacy of Trametinib in NRAS-Mutant Melanoma Cell Lines

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2012
Author(s):  
Kathryn M. Appleton ◽  
Charuta C. Palsuledesai ◽  
Sean A. Misek ◽  
Maja Blake ◽  
Joseph Zagorski ◽  
...  
Keyword(s):  
Cell Lines ◽  
Melanoma Cell ◽  
Therapeutic Potential ◽  
Mapk Pathway ◽  
Mek Inhibitor ◽  
Intrinsic Resistance ◽  
Primary Resistance ◽  
Induced Apoptosis ◽  
Melanoma Cell Lines

The Ras/MEK/ERK pathway has been the primary focus of targeted therapies in melanoma; it is aberrantly activated in almost 80% of human cutaneous melanomas (≈50% BRAFV600 mutations and ≈30% NRAS mutations). While drugs targeting the MAPK pathway have yielded success in BRAFV600 mutant melanoma patients, such therapies have been ineffective in patients with NRAS mutant melanomas in part due to their cytostatic effects and primary resistance. Here, we demonstrate that increased Rho/MRTF-pathway activation correlates with high intrinsic resistance to the MEK inhibitor, trametinib, in a panel of NRAS mutant melanoma cell lines. A combination of trametinib with the Rho/MRTF-pathway inhibitor, CCG-222740, synergistically reduced cell viability in NRAS mutant melanoma cell lines in vitro. Furthermore, the combination of CCG-222740 with trametinib induced apoptosis and reduced clonogenicity in SK-Mel-147 cells, which are highly resistant to trametinib. These findings suggest a role of the Rho/MRTF-pathway in intrinsic trametinib resistance in a subset of NRAS mutant melanoma cell lines and highlight the therapeutic potential of concurrently targeting the Rho/MRTF-pathway and MEK in NRAS mutant melanomas.

scholarly journals Phytochemicals inhibit migration of triple negative breast cancer cells by targeting kinase signaling

BMC Cancer ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Pradip Shahi Thakuri ◽  
Megha Gupta ◽  
Sunil Singh ◽  
Ramila Joshi ◽  
Eric Glasgow ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Migration ◽  
Cancer Cells ◽  
Protein Kinases ◽  
Cell Lines ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Migration And Invasion ◽  
Tnbc Cell

Abstract Background Cell migration and invasion are essential processes for metastatic dissemination of cancer cells. Significant progress has been made in developing new therapies against oncogenic signaling to eliminate cancer cells and shrink tumors. However, inherent heterogeneity and treatment-induced adaptation to drugs commonly enable subsets of cancer cells to survive therapy. In addition to local recurrence, these cells escape a primary tumor and migrate through the stroma to access the circulation and metastasize to different organs, leading to an incurable disease. As such, therapeutics that block migration and invasion of cancer cells may inhibit or reduce metastasis and significantly improve cancer therapy. This is particularly more important for cancers, such as triple negative breast cancer, that currently lack targeted drugs. Methods We used cell migration, 3D invasion, zebrafish metastasis model, and phosphorylation analysis of 43 protein kinases in nine triple negative breast cancer (TNBC) cell lines to study effects of fisetin and quercetin on inhibition of TNBC cell migration, invasion, and metastasis. Results Fisetin and quercetin were highly effective against migration of all nine TNBC cell lines with up to 76 and 74% inhibitory effects, respectively. In addition, treatments significantly reduced 3D invasion of highly motile TNBC cells from spheroids into a collagen matrix and their metastasis in vivo. Fisetin and quercetin commonly targeted different components and substrates of the oncogenic PI3K/AKT pathway and significantly reduced their activities. Additionally, both compounds disrupted activities of several protein kinases in MAPK and STAT pathways. We used molecular inhibitors specific to these signaling proteins to establish the migration-inhibitory role of the two phytochemicals against TNBC cells. Conclusions We established that fisetin and quercetin potently inhibit migration of metastatic TNBC cells by interfering with activities of oncogenic protein kinases in multiple pathways.

Therapeutic potential of recombinant thrombomodulin for lung injury after pneumonectomy via inhibition of high-mobility group box 1 in mice

2016 ◽  
Vol 81 (5) ◽  
pp. 868-875 ◽  
Author(s):  
Yusuke Takahashi ◽  
Noriyuki Matsutani ◽  
Hitoshi Dejima ◽  
Takashi Nakayama ◽  
Ryo Okamura ◽  
...  
Keyword(s):  
Lung Injury ◽  
Therapeutic Potential ◽  
High Mobility ◽  
High Mobility Group ◽  
Recombinant Thrombomodulin

scholarly journals Antileukemic Effect of Tualang Honey on Acute and Chronic Leukemia Cell Lines

2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
Nik Muhd Khuzaimi Nik Man ◽  
Rosline Hassan ◽  
Cheng Yong Ang ◽  
Abu Dzarr Abdullah ◽  
Muhammad Amiro Rasheeq Mohd Radzi ◽  
...  
Keyword(s):  
Cell Lines ◽  
Mononuclear Cell ◽  
Therapeutic Potential ◽  
Morphological Changes ◽  
Leukemia Cell ◽  
Chronic Leukemia ◽  
Human Mononuclear Cell ◽  
Leukemia Cell Lines ◽  
Antileukemic Effect ◽  
Tualang Honey

Complementary medicine using natural product as antitumor is on the rise. Much research has been performed on Tualang Honey and it was shown to have therapeutic potential in wound healing, and antimicrobial activity and be antiproliferative against several cancer models such as human osteosarcoma (HOS), human breast (MCF-7 and MDA-MB-231), and cervical (HeLa) cancer cell lines. To date, there was limited study on antileukemic properties of Tualang (Koompassia excelsa) Honey. The aim of this study was to evaluate the antileukemic effect of Tualang Honey on acute and chronic leukemia cell lines. Leukemia cell lines (K562 and MV4-11) and human mononuclear cell isolated from peripheral blood were grown in RPM1 1640 culture medium. The cells were incubated with increasing concentrations of Tualang Honey. After incubation, the evaluation of viability and apoptosis was performed. The morphological changes of leukemia cells were the presence of cytoplasmic blebs followed by apoptotic bodies and round shape of cells. IC50against K562 and MV4-11 was determined. Tualang Honey gave 53.9% and 50.6% apoptosis activity on K562 and MV4-11, respectively, while on human mononuclear cell it was 37.4%. Tualang Honey has the apoptosis-inducing ability for acute and chronic myeloid leukemia (K562 and MV4-11) cell lines.

Natural products targeting cancer stem cells: a revisit

2021 ◽  
Vol 28 ◽  
Author(s):  
Jiahua Cui ◽  
Jiajun Qian ◽  
Larry Ming-Cheung Chow ◽  
Jinping Jia
Keyword(s):  
Stem Cells ◽  
Drug Resistance ◽  
Natural Products ◽  
Cancer Stem Cells ◽  
Therapeutic Potential ◽  
Tumor Development ◽  
Biologically Active ◽  
Cellular Targets ◽  
Drug Candidates ◽  
Enhanced Expression

Background: The proposed central role of cancer stem cells (CSCs) in tumor development has been extended to explain the diverse oncologic phenomena such as multidrug resistance, metastasis and tumor recurrence in clinics. Due to the enhanced expression of ATP-binding cassette transporters and anti-apoptotic factors, stagnation on G0 phase and the strong ability of self-renewal, the CSCs were highly resistant to clinical anticancer drugs. Therefore, the discovery of new drug candidates that could effectively eradicate cancer stem cells afforded promising outcomes in cancer therapy. Introduction: Natural products and their synthetic analogues are a rich source of biologically active compounds and several of them have already been recognized as potent CSCs killers. We aim to provide a collection of recently identified natural products that suppressed the survival of the small invasive CSC populations and combated the drug resistance of these cells in chemotherapy. Results and Conclusion: These anti-CSCs natural products included flavonoids, stilbenes, quinones, terpenoids, polyketide antibiotics, steroids and alkaloids. In the present review, we highlighted the therapeutic potential of natural products and their derivatives against the proliferation and drug resistance of CSCs, their working mechanisms and related structure-activity relationships. Meanwhile, in this survey, several natural products with diverse cellular targets such as the naphthoquinone shikonin and the stilbene resveratrol were characterized as promising lead compounds for future development.

Sign in / Sign up

Export Citation Format

Share Document