Extracellular Granzyme A Promotes Colorectal Cancer Development by Enhancing Gut Inflammation

Santiago, Llipsy; Castro, Marta; Sanz‐Pamplona, Rebeca; Garzón, Marcela; Ramírez-Labrada, Ariel; Tapia, Elena; Moreno, Vı́ctor; Layunta, Elena; Gil‐Gómez, Gabriel; Garrido, Marta; Peña, Raúl; Lanuza, Pilar M.; Comas, Laura; Jaime-Sánchez, Paula; Uranga-Murillo, Iratxe; Campo, Rosa del; Pelegrı́n, Pablo; Camerer, Eric; Martínez-Lostao, Luis; Muñoz, Guillermo; Uranga, José Antonio; Alcalde, Anabel; Gálvez, Eva M.; Ferrández, Ángel; Bird, Phillip I.; Metkar, Sunil S.; Arias, Maykel; Pardo, Julián

doi:10.1016/j.celrep.2020.107847

Cited by 44 publications

(40 citation statements)

References 75 publications

(81 reference statements)

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“…28 Yang et al 29 reported that tumor-associated macrophages can activate STAT3 in tumor cells through paracrine pathways and subsequently upregulate SOX2 expression. Santiago et al 30 found that extracellular NF-jB-dependent IL-6 production promoted STAT3 activation in colorectal cancer cells. IL-6, an important inflammatory factor, has been reported to be highly expressed in patients with lung cancer who have a poor prognosis.…”

Section: Discussionmentioning

confidence: 99%

Nelfinavir restricts A549 cell growth by inhibiting STAT3 signaling

Wang

et al. 2021

J Int Med Res

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Objective To investigate the anticancer effect of nelfinavir (NFV) on human A549 cells. Methods The inhibitory effects of NFV on the proliferation of human A549 cells were assessed using a MTT assay. Apoptotic cells were observed by fluorescence microscopy following Hoechst 33342 staining. Apoptosis of A549 cells was assessed using Annexin-V/propidium iodide staining and flow cytometry. Expression levels of signal transducer and activator of transcription 3 (STAT3) and p-STAT3 were measured by western blotting. STAT3 RNA silencing was used to investigate the pro-apoptotic mechanism of NFV in A549 cells. Results NFV dose-dependently suppressed proliferation of human A549 cells and induced significant apoptosis. Western blotting showed that the antitumor function of NFV might be mediated by STAT3 inhibition. A549 cell apoptosis in response to 20 µM NFV was significantly increased following STAT3 silencing. NFV significantly impeded the expression of the anti-apoptotic proteins Bcl-xL and Bcl-2, by increased the expression of the pro-apoptotic protein Cle-PARP. Conclusions Our findings highlight STAT3 as a promising therapeutic target. NFV is a novel anti-cancer drug for the treatment of non-small-cell lung cancer.

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Section: Discussionmentioning

confidence: 99%

Nelfinavir restricts A549 cell growth by inhibiting STAT3 signaling

Wang

et al. 2021

J Int Med Res

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“…STAT3 and NF-κB have previously been shown to be activated in macrophages by recombinant GzmA in vitro (Santiago et al, 2020), with monocytes/macrophages reported as targets for GzmA activity in a variety of settings (Garzon-Tituana et al, 2021;Metkar et al, 2008;Santiago et al, 2017;Spencer et al, 2013;Uranga et al, 2016). Interrogation of the Molecular Signature Database (MSigDB) (Subramanian et al, 2005) also found genesets associated with activated monocytes (GSE19888) significantly enriched in the down-regulated genes for GzmA S211A vs 6J mice by preranked (fold change) GSEAs (Supplementary Fig.…”

Section: Immune/inflammation Signatures Stimulated By Circulating Proteolytically Active Gzmamentioning

confidence: 94%

“…Like granzyme B (GzmB), GzmA has thus been classified as a cytotoxic granzyme (Golstein and Griffiths, 2018;Mpande et al, 2018;Muraro et al, 2017;Zhou et al, 2020), although in several studies a role for GzmA in mediating cellular cytotoxicity was not observed (Ebnet et al, 1995;Joeckel and Bird, 2014;Regner et al, 2009;Regner et al, 2011;Smyth et al, 2003). In a range of settings GzmA has also been associated with the promotion of inflammation, providing an additional or alternative view of its physiological role, although consensus on mechanisms has remained elusive (Metkar et al, 2008;Park et al, 2020;Santiago et al, 2020;Santiago et al, 2017;Schanoski et al, 2019;Shimizu et al, 2019; van Daalen et al, 2020;Wensink et al, 2015;Wilson et al, 2017), with a number of potential intracellular and extracellular targets for GzmA reported. These include pro-IL-1β (Hildebrand et al, 2014), SET complex proteins (Mandrup-Poulsen, 2017;Mollah et al, 2017), gasdermin B (Zhou et al, 2020), mitochondrial complex I protein NDUFS3 (Martinvalet et al, 2008), protease activated receptors (Hansen et al, 2005;Sower et al, 1996;Suidan et al, 1994;Suidan et al, 1996), TLR2/4 (van Eck et al, 2017) and TLR9 (Shimizu et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

“…These include pro-IL-1β (Hildebrand et al, 2014), SET complex proteins (Mandrup-Poulsen, 2017;Mollah et al, 2017), gasdermin B (Zhou et al, 2020), mitochondrial complex I protein NDUFS3 (Martinvalet et al, 2008), protease activated receptors (Hansen et al, 2005;Sower et al, 1996;Suidan et al, 1994;Suidan et al, 1996), TLR2/4 (van Eck et al, 2017) and TLR9 (Shimizu et al, 2019). GzmA -/mice have also been used to show a role for GzmA in inter alia diabetes (Mollah et al, 2017), cancer (Santiago et al, 2020), bacterial infections (Garcia-Laorden et al, 2016;Garcia-Laorden et al, 2017;van den Boogaard et al, 2016) and arthritis (Santiago et al, 2017). GzmA's bioactivity has generally (Plasman et al, 2014;Schanoski et al, 2019;Zhou et al, 2020), but not always (Shimizu et al, 2019;van Eck et al, 2017), been associated with GzmA's protease activity, with circulating GzmA in humans shown to be proteolytically active (Spaeny-Dekking et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

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An inconvenient association between granzyme A and Nicotinamide Nucleotide Transhydrogenase

Rawle

Dumenil

et al. 2021

Preprint

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Granzyme A (GzmA) is a serine protease secreted by cytotoxic lymphocytes, with GzmA-/- mouse studies informing our understanding of GzmAs physiological function. We show herein that GzmA-/- mice have a mixed C57BL/6J and C57BL/6N background and retain the full length Nicotinamide Nucleotide Transhydrogenase (Nnt) gene, whereas Nnt is truncated in C57BL/6J mice. Chikungunya viral arthritis was substantially ameliorated in GzmA-/- mice; however, the presence of Nnt, rather than loss of GzmA, was responsible for this phenotype by constraining lymphocyte infiltration. A new CRISPR active site mutant C57BL/6J GzmAS211A mouse provided the first insights into GzmAs bioactivity free of background issues, with circulating proteolytically active GzmA promoting immune-stimulating and pro-inflammatory signatures. Remarkably, k-mer mining of the Sequence Read Archive illustrated that ~27% of Run Accessions and ~38% of Bioprojects listing C57BL/6J as the mouse strain, had Nnt sequencing reads inconsistent with a C57BL/6J background. The Nnt issue has clearly complicated our understanding of GzmA and may similarly have influenced studies across a broad range of fields.

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“…Noteworthy, GrB (18,21,77), as some other granzymes (78)(79)(80), has been recently proposed as promoters of EMT, an important process linked the stimulation of the three following events: 1) tissue and organ formation during embryogenesis; 2) tissue and organ physiologic repair and pathologic fibrosis; 3) tumor cell invasion and metastasis (81). EMT is a process in which epithelial cells lose E-cadherin-mediated cell-cell adhesion and acquire some mesenchymal features, as N-cadherin expression and the capability of invasion, migration, and production of ECM.…”

Section: Granzyme B: Epithelial-to-mesenchymal Transition and Fibrosimentioning

confidence: 99%

Granzyme B in Inflammatory Diseases: Apoptosis, Inflammation, Extracellular Matrix Remodeling, Epithelial-to-Mesenchymal Transition and Fibrosis

et al. 2020

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Inflammation is strictly interconnected to anti-inflammatory mechanisms to maintain tissue homeostasis. The disruption of immune homeostasis can lead to acute and chronic inflammatory diseases, as cardiovascular, pulmonary, metabolic diseases and cancer. The knowledge of the mechanisms involved in the development and progression of these pathological conditions is important to find effective therapies. Granzyme B (GrB) is a serine protease produced by a variety of immune, non-immune and tumor cells. Apoptotic intracellular and multiple extracellular functions of GrB have been recently identified. Its capability of cleaving extracellular matrix (ECM) components, cytokines, cell receptors and clotting proteins, revealed GrB as a potential multifunctional pro-inflammatory molecule with the capability of contributing to the pathogenesis of different inflammatory conditions, including inflammaging, acute and chronic inflammatory diseases and cancer. Here we give an overview of recent data concerning GrB activity on multiple targets, potentially allowing this enzyme to regulate a wide range of crucial biological processes that play a role in the development, progression and/or severity of inflammatory diseases. We focus our attention on the promotion by GrB of perforin-dependent and perforin-independent (anoikis) apoptosis, inflammation derived by the activation of some cytokines belonging to the IL-1 cytokine family, ECM remodeling, epithelial-to-mesenchymal transition (EMT) and fibrosis. A greater comprehension of the pathophysiological consequences of GrB-mediated multiple activities may favor the design of new therapies aim to inhibit different inflammatory pathological conditions such as inflammaging and age-related diseases, EMT and organ fibrosis.

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Extracellular Granzyme A Promotes Colorectal Cancer Development by Enhancing Gut Inflammation

Cited by 44 publications

References 75 publications

Nelfinavir restricts A549 cell growth by inhibiting STAT3 signaling

Nelfinavir restricts A549 cell growth by inhibiting STAT3 signaling

An inconvenient association between granzyme A and Nicotinamide Nucleotide Transhydrogenase

Granzyme B in Inflammatory Diseases: Apoptosis, Inflammation, Extracellular Matrix Remodeling, Epithelial-to-Mesenchymal Transition and Fibrosis

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