Publications by authors named "Suravi Chakrabarty"

8 Publications

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Diverse and converging roles of ERK1/2 and ERK5 pathways on mesenchymal to epithelial transition in breast cancer.

Transl Oncol 2021 Jun 21;14(6):101046. Epub 2021 Mar 21.

Department of Pharmacology, School of Pharmacy, Duquesne University, Pittsburgh, PA 15219, USA. Electronic address:

The epithelial to mesenchymal transition (EMT) is characterized by a loss of cell polarity, a decrease in the epithelial cell marker E-cadherin, and an increase in mesenchymal markers including the zinc-finger E-box binding homeobox (ZEB1). The EMT is also associated with an increase in cell migration and anchorage-independent growth. Induction of a reversal of the EMT, a mesenchymal to epithelial transition (MET), is an emerging strategy being explored to attenuate the metastatic potential of aggressive cancer types, such as triple-negative breast cancers (TNBCs) and tamoxifen-resistant (TAMR) ER-positive breast cancers, which have a mesenchymal phenotype. Patients with these aggressive cancers have poor prognoses, quick relapse, and resistance to most chemotherapeutic drugs. Overexpression of extracellular signal-regulated kinase (ERK) 1/2 and ERK5 is associated with poor patient survival in breast cancer. Moreover, TNBC and tamoxifen resistant cancers are unresponsive to most targeted clinical therapies and there is a dire need for alternative therapies. In the current study, we found that MAPK3, MAPK1, and MAPK7 gene expression correlated with EMT markers and poor overall survival in breast cancer patients using publicly available datasets. The effect of ERK1/2 and ERK5 pathway inhibition on MET was evaluated in MDA-MB-231, BT-549 TNBC cells, and tamoxifen-resistant MCF-7 breast cancer cells. Moreover, TU-BcX-4IC patient-derived primary TNBC cells were included to enhance the translational relevance of our study. We evaluated the effect of pharmacological inhibitors and lentivirus-induced activation or inhibition of the MEK1/2-ERK1/2 and MEK5-ERK5 pathways on cell morphology, E-cadherin, vimentin and ZEB1 expression. Additionally, the effects of pharmacological inhibition of trametinib and XMD8-92 on nuclear localization of ERK1/2 and ERK5, cell migration, proliferation, and spheroid formation were evaluated. Novel compounds that target the MEK1/2 and MEK5 pathways were used in combination with the AKT inhibitor ipatasertib to understand cell-specific responses to kinase inhibition. The results from this study will aid in the design of innovative therapeutic strategies that target cancer metastases.
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http://dx.doi.org/10.1016/j.tranon.2021.101046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020482PMC
June 2021

Controlled Inhibition of Apoptosis by Photoactivatable Caspase Inhibitors.

Cell Chem Biol 2020 11 18;27(11):1434-1440.e10. Epub 2020 Aug 18.

KU Leuven, Department of Cellular and Molecular Medicine, Laboratory of Chemical Biology, Herestraat 49 Box 802, 3000 Leuven, Belgium; Leibniz Institute for Analytical Sciences ISAS, e.V., Otto-Hahn-Strasse 6b, 44227 Dortmund, Germany. Electronic address:

Caspases control regulated cell death (apoptosis), a process that is crucial in the development of multicellular organisms as well as in various diseases. In order to spatiotemporally study apoptosis, we here develop photoactivatable caspase inhibitors. These are based on cysteine-reactive acyloxymethyl ketone electrophiles connected to a peptide targeting caspases. Importantly, the aspartate crucial for recognition by caspases is caged with a photoprotecting group. Ester photocages were found to be labile, and it was critical to have a nitroindoline cage, which forms a stable amide bond with the aspartate side chain. The nitroindoline-protected inhibitors lead to an efficient turn-on of inhibitory activity after irradiation with light. They are applicable in live cells, where they prevent anti-FAS-induced apoptosis only upon irradiation. Overall, these reagents will allow a better understanding of the spatial and temporal dimensions of apoptosis in complex, dynamic systems.
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http://dx.doi.org/10.1016/j.chembiol.2020.08.001DOI Listing
November 2020

Pharmacological inhibition of the MEK5/ERK5 and PI3K/Akt signaling pathways synergistically reduces viability in triple-negative breast cancer.

J Cell Biochem 2020 02 28;121(2):1156-1168. Epub 2019 Aug 28.

Department of Pharmacology and Toxicology, Duquesne University, Pittsburgh, Pennsylvania.

Triple-negative breast cancers (TNBCs) represent 15% to 20% of all breast cancers and are often associated with poor prognosis. The lack of targeted therapies for TNBCs contributes to higher mortality rates. Aberrations in the phosphoinositide-3-kinase (PI3K) and mitogen-activated protein kinase pathways have been linked to increased breast cancer proliferation and survival. It has been proposed that these survival characteristics are enhanced through compensatory signaling and crosstalk mechanisms. While the crosstalk between PI3K and extracellular signal-regulated kinase 1/2 (ERK1/2) pathways has been characterized in several systems, new evidence suggests that MEK5/ERK5 signaling is a key component in the proliferation and survival of several aggressive cancers. In this study, we examined the effects of dual inhibition of PI3K/protein kinase B (Akt) and MEK5/ERK5 in the MDA-MB-231, BT-549, and MDA-MB-468 TNBC cell lines. We used the Akt inhibitor ipatasertib, ERK5 inhibitors XMD8-92 and AX15836, and the novel MEK5 inhibitor SC-1-181 to investigate the effects of dual inhibition. Our results indicated that dual inhibition of PI3K/Akt and MEK5/ERK5 signaling was more effective at reducing the proliferation and survival of TNBCs than single inhibition of either pathway alone. In particular, a loss of Bad phosphorylation at two distinct sites was observed with dual inhibition. Furthermore, the inhibition of both pathways led to p21 restoration, decreased cell proliferation, and induced apoptosis. In addition, the dual inhibition strategy was determined to be synergistic in MDA-MB-231 and BT-549 cells and was relatively nontoxic in the nonneoplastic MCF-10 cell line. In summary, the results from this study provide a unique prospective into the utility of a novel dual inhibition strategy for targeting TNBCs.
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http://dx.doi.org/10.1002/jcb.29350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6923606PMC
February 2020

Novel Diphenylamine Analogs Induce Mesenchymal to Epithelial Transition in Triple Negative Breast Cancer.

Front Oncol 2019 30;9:672. Epub 2019 Jul 30.

Division of Medicinal Chemistry, School of Pharmacy, Duquesne University, Pittsburgh, PA, United States.

Epithelial to mesenchymal transition (EMT) is a cellular program that converts non-motile epithelial cells into invasive mesenchymal cells. EMT is implicated in cancer metastasis, chemo-resistance, cancer progression, and generation of cancer stem cells (CSCs). Inducing mesenchymal to epithelial transition (MET), the reverse phenomenon of EMT, is proposed as a novel strategy to target triple negative and tamoxifen-resistant breast cancer. Triple negative breast cancer (TNBC) is characterized by the loss of hormone receptors, a highly invasive mesenchymal phenotype, and a lack of targeted therapy. Estrogen receptor-positive breast cancer can be targeted by tamoxifen, an ER antagonist. However, these cells undergo EMT over the course of treatment and develop resistance. Thus, there is an urgent need to develop therapeutic interventions to target these aggressive cancers. In this study, we examined the role of novel diphenylamine analogs in converting the mesenchymal phenotype of MDA-MB-231 TNBC cells to a lesser aggressive epithelial phenotype. Using analog-based drug design, a series of diphenylamine analogs were synthesized and initially evaluated for their effect on E-cadherin protein expression and changes incell morphology, which was quantified by measuring the spindle index (SI) value. Selected compound from this series increases the expression of E-cadherin, a primary marker for epithelial cells, and decreases the mesenchymal markers SOX2, ZEB1, Snail, and vimentin. The increase in epithelial markers and the decrease in mesenchymal markers are consistent with a phenotypic switch from spindle-like morphology to cobblestone-like morphology. Furthermore, Compound decreases spheroid viability, cell migration, and cell proliferation in triple negative BT-549 and tamoxifen-resistant MCF-7 breast cancer cells.
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http://dx.doi.org/10.3389/fonc.2019.00672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6682674PMC
July 2019

Short Peptides with Uncleavable Peptide Bond Mimetics as Photoactivatable Caspase-3 Inhibitors.

Molecules 2019 Jan 8;24(1). Epub 2019 Jan 8.

Leibniz-Institut für Analytische Wissenschaften ISAS, Otto-Hahn-Str. 6b, 44227 Dortmund, Germany.

Chemical probes that covalently interact with proteases have found increasing use for the study of protease function and localization. The design and synthesis of such probes is still a bottleneck, as the strategies to target different families are highly diverse. We set out to design and synthesize chemical probes based on protease substrate specificity with inclusion of an uncleavable peptide bond mimic and a photocrosslinker for covalent modification of the protease target. With caspase-3 as a model target protease, we designed reduced amide and triazolo peptides as substrate mimetics, whose sequences can be conveniently constructed by modified solid phase peptide synthesis. We found that these probes inhibited the caspase-3 activity, but did not form a covalent bond. It turned out that the reduced amide mimics, upon irradiation with a benzophenone as photosensitizer, are oxidized and form low concentrations of peptide aldehydes, which then act as inhibitors of caspase-3. This type of photoactivation may be utilized in future photopharmacology experiments to form protease inhibitors at a precise time and location.
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http://dx.doi.org/10.3390/molecules24010206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6337261PMC
January 2019

Recent Advances in Activity-Based Protein Profiling of Proteases.

Curr Top Microbiol Immunol 2019;420:253-281

Laboratory of Chemical Biology, Department of Cellular & Molecular Medicine, KU Leuven-University of Leuven, Herestraat 49, Box 802, 3000, Louvain, Belgium.

The activity of proteases is tightly regulated, and dysregulation is linked to a variety of human diseases. For this reason, ABPP is a well-suited method to study protease biology and the design of protease probes has pushed the boundaries of ABPP. The development of highly selective protease probes is still a challenging task. After an introduction, the first section of this chapter discusses several strategies to enable detection of a single active protease species. These range from the usage of non-natural amino acids, combination of probes with antibodies, and engineering of the target proteases. A next section describes the different types of detection tags that facilitate the read-out possibilities including various types of imaging methods and mass spectrometry-based target identification. The power of protease ABPP is illustrated by examples for a selected number of proteases. It is expected that some protease probes that have been evaluated in animal models of human disease will find translation into clinical application in the near future.
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http://dx.doi.org/10.1007/82_2018_138DOI Listing
August 2019

Structure activity relationships of anthranilic acid-based compounds on cellular and in vivo mitogen activated protein kinase-5 signaling pathways.

Bioorg Med Chem Lett 2018 07 20;28(13):2294-2301. Epub 2018 May 20.

Department of Pharmacology, School of Pharmacy, Duquesne University, 410A Mellon Hall, 600 Forbes Ave., Pittsburgh, PA 15282, United States.

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http://dx.doi.org/10.1016/j.bmcl.2018.05.029DOI Listing
July 2018

Catalytic Isonitrile Insertions and Condensations Initiated by RNC-X Complexation.

Adv Synth Catal 2014 Jul 20;356(10):2135-2196. Epub 2014 Jun 20.

Department of Chemistry, Duquesne University, Pittsburgh, PA 15282-1530, USA.

Isonitriles are delicately poised chemical entities capable of being coaxed to react as nucleophiles or electrophiles. Directing this tunable reactivity with metal and non-metal catalysts provides rapid access to a large array of complex nitrogenous structures ideally functionalized for medicinal applications. Isonitrile insertion into transition metal complexes has featured in numerous synthetic and mechanistic studies, leading to rapid deployment of isonitriles in numerous catalytic processes, including multicomponent reactions (MCR). Covering the literature from 1990-2014, the present review collates reaction types to highlight reactivity trends and allow catalyst comparison.
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http://dx.doi.org/10.1002/adsc.201400017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4251577PMC
July 2014
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