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Article ; Online: Protein Kinase C at the Crossroad of Mutations, Cancer, Targeted Therapy and Immune Response

Aquino, Angelo / Bianchi, Nicoletta / Terrazzan, Anna / Franzese, Ornella

Biology (Basel). 2023 July 26, v. 12, no. 8

2023

Abstract: The frequent PKC dysregulations observed in many tumors have made these enzymes natural targets for anticancer applications. Nevertheless, this considerable interest in the development of PKC modulators has not led to the expected therapeutic benefits, ... ...

Abstract	The frequent PKC dysregulations observed in many tumors have made these enzymes natural targets for anticancer applications. Nevertheless, this considerable interest in the development of PKC modulators has not led to the expected therapeutic benefits, likely due to the complex biological activities regulated by PKC isoenzymes, often playing ambiguous and protective functions, further driven by the occurrence of mutations. The structure, regulation and functions of PKCs have been extensively covered in other publications. Herein, we focused on PKC alterations mostly associated with complete functional loss. We also addressed the modest yet encouraging results obtained targeting PKC in selected malignancies and the more frequent negative clinical outcomes. The reported observations advocate the need for more selective molecules and a better understanding of the involved pathways. Furthermore, we underlined the most relevant immune mechanisms controlled by PKC isoforms potentially impacting the immune checkpoint inhibitor blockade-mediated immune recovery. We believe that a comprehensive examination of the molecular features of the tumor microenvironment might improve clinical outcomes by tailoring PKC modulation. This approach can be further supported by the identification of potential response biomarkers, which may indicate patients who may benefit from the manipulation of distinctive PKC isoforms.
Keywords	biomarkers ; immune response ; isozymes ; neoplasms ; protein kinase C ; therapeutics
Language	English
Dates of publication	2023-0726
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article ; Online
ZDB-ID	2661517-4
ISSN	2079-7737
ISSN	2079-7737
DOI	10.3390/biology12081047
Database	NAL-Catalogue (AGRICOLA)

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Article: Protein Kinase C at the Crossroad of Mutations, Cancer, Targeted Therapy and Immune Response.

Aquino, Angelo / Bianchi, Nicoletta / Terrazzan, Anna / Franzese, Ornella

Biology

2023 Volume 12, Issue 8

Abstract	The frequent PKC dysregulations observed in many tumors have made these enzymes natural targets for anticancer applications. Nevertheless, this considerable interest in the development of PKC modulators has not led to the expected therapeutic benefits, likely due to the complex biological activities regulated by PKC isoenzymes, often playing ambiguous and protective functions, further driven by the occurrence of mutations. The structure, regulation and functions of PKCs have been extensively covered in other publications. Herein, we focused on PKC alterations mostly associated with complete functional loss. We also addressed the modest yet encouraging results obtained targeting PKC in selected malignancies and the more frequent negative clinical outcomes. The reported observations advocate the need for more selective molecules and a better understanding of the involved pathways. Furthermore, we underlined the most relevant immune mechanisms controlled by PKC isoforms potentially impacting the immune checkpoint inhibitor blockade-mediated immune recovery. We believe that a comprehensive examination of the molecular features of the tumor microenvironment might improve clinical outcomes by tailoring PKC modulation. This approach can be further supported by the identification of potential response biomarkers, which may indicate patients who may benefit from the manipulation of distinctive PKC isoforms.
Language	English
Publishing date	2023-07-26
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2661517-4
ISSN	2079-7737
ISSN	2079-7737
DOI	10.3390/biology12081047
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Article ; Online: State-of-the-art in transposable element modulation affected by drugs in malignant prostatic cancer cells.

Terrazzan, Anna / Vanini, Riccardo / Ancona, Pietro / Bianchi, Nicoletta / Taccioli, Cristian / Aguiari, Gianluca

Journal of cellular biochemistry

2024 Volume 125, Issue 5, Page(s) e30557

Abstract: Over recent years, the investigation of transposable elements (TEs) has granted researchers a deeper comprehension of their characteristics and functions, particularly regarding their significance in the mechanisms contributing to cancer development. ... ...

Abstract	Over recent years, the investigation of transposable elements (TEs) has granted researchers a deeper comprehension of their characteristics and functions, particularly regarding their significance in the mechanisms contributing to cancer development. This manuscript focuses on prostate carcinoma cell lines and offers a comprehensive review intended to scrutinize the associations and interactions between TEs and genes, as well as their response to treatment using various chemical drugs, emphasizing their involvement in cancer progression. We assembled a compendium of articles retrieved from the PubMed database to construct networks demonstrating correlations with genes and pharmaceuticals. In doing so, we linked the transposition of certain TE types to the expression of specific transcripts directly implicated in carcinogenesis. Additionally, we underline that treatment employing different drugs revealed unique patterns of TE reactivation. Our hypothesis gathers the current understanding and guides research toward evidence-based investigations, emphasizing the association between antiviral drugs, chemotherapy, and the reduced expression of TEs in patients affected by prostate cancer.
MeSH term(s)	Humans ; Prostatic Neoplasms/genetics ; Prostatic Neoplasms/drug therapy ; Prostatic Neoplasms/metabolism ; Prostatic Neoplasms/pathology ; Male ; DNA Transposable Elements ; Gene Expression Regulation, Neoplastic/drug effects ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Cell Line, Tumor
Chemical Substances	DNA Transposable Elements ; Antineoplastic Agents
Language	English
Publishing date	2024-03-19
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	392402-6
ISSN	1097-4644 ; 0730-2312
ISSN (online)	1097-4644
ISSN	0730-2312
DOI	10.1002/jcb.30557
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Zs.A 1114: Show issues

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Article ; Online: Inverse Impact of Cancer Drugs on Circular and Linear RNAs in Breast Cancer Cell Lines.

Terrazzan, Anna / Crudele, Francesca / Corrà, Fabio / Ancona, Pietro / Palatini, Jeffrey / Bianchi, Nicoletta / Volinia, Stefano

Non-coding RNA

2023 Volume 9, Issue 3

Abstract: Altered expression of circular RNAs (circRNAs) has previously been investigated in breast cancer. However, little is known about the effects of drugs on their regulation and relationship with the cognate linear transcript (linRNA). We analyzed the ... ...

Abstract	Altered expression of circular RNAs (circRNAs) has previously been investigated in breast cancer. However, little is known about the effects of drugs on their regulation and relationship with the cognate linear transcript (linRNA). We analyzed the dysregulation of both 12 cancer-related circRNAs and their linRNAs in two breast cancer cell lines undergoing various treatments. We selected 14 well-known anticancer agents affecting different cellular pathways and examined their impact. Upon drug exposure circRNA/linRNA expression ratios increased, as a result of the downregulation of linRNA and upregulation of circRNA within the same gene. In this study, we highlighted the relevance of identifying the drug-regulated circ/linRNAs according to their oncogenic or anticancer role. Interestingly,
Language	English
Publishing date	2023-05-19
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2813993-8
ISSN	2311-553X ; 2311-553X
ISSN (online)	2311-553X
ISSN	2311-553X
DOI	10.3390/ncrna9030032
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Article ; Online: Transcriptomics Studies Reveal Functions of Transglutaminase 2 in Breast Cancer Cells Using Membrane Permeable and Impermeable Inhibitors.

Ancona, Pietro / Trentini, Alessandro / Terrazzan, Anna / Grassilli, Silvia / Navals, Pauline / Gates, Eric W J / Rosta, Valentina / Cervellati, Carlo / Bergamini, Carlo M / Pignatelli, Angela / Keillor, Jeffrey W / Taccioli, Cristian / Bianchi, Nicoletta

Journal of molecular biology

2024 Volume 436, Issue 10, Page(s) 168569

Abstract: Transglutaminase 2 (TG2) performs many functions both under physiological and pathological conditions. In cancer, its expression is associated with aggressiveness, propensity to epithelial-mesenchymal transition, and metastasis. Since TG2 performs key ... ...

Abstract	Transglutaminase 2 (TG2) performs many functions both under physiological and pathological conditions. In cancer, its expression is associated with aggressiveness, propensity to epithelial-mesenchymal transition, and metastasis. Since TG2 performs key functions both outside and inside the cell, using inhibitors with different membrane permeability we analyzed the changes in the transcriptome induced in two triple-negative cell lines (MDA-MB-436 and MDA-MB-231) with aggressive features. By characterizing pathways and gene networks, we were able to define the effects of TG2 inhibitors (AA9, membrane-permeable, and NCEG2, impermeable) in relation to the roles of the enzyme in the intra- and extracellular space within the context of breast cancer. The deregulated genes revealed p53 and integrin signaling to be the common pathways with some genes showing opposite changes in expression. In MDA-MB-436, AA9 induced apoptosis, modulated cadherin, Wnt, gastrin and cholecystokinin receptors (CCKR) mediated signaling, with RHOB and GNG2 playing significant roles, and affected the Warburg effect by decreasing glycolytic enzymes. In MDA-MB-231 cells, AA9 strongly impacted HIF-mediated hypoxia, including AKT and mTOR pathway. These effects suggest an anti-tumor activity by blocking intracellular TG2 functions. Conversely, the use of NCEG2 stimulated the expression of ATP synthase and proteins involved in DNA replication, indicating a potential promotion of cell proliferation through inhibition of extracellular TG2. To effectively utilize these molecules as an anti-tumor strategy, an appropriate delivery system should be evaluated to target specific functions and avoid adverse effects. Additionally, considering combinations with other pathway modulators is crucial.
MeSH term(s)	Humans ; Protein Glutamine gamma Glutamyltransferase 2 ; Transglutaminases/metabolism ; Transglutaminases/genetics ; GTP-Binding Proteins/metabolism ; GTP-Binding Proteins/genetics ; Cell Line, Tumor ; Female ; Gene Expression Regulation, Neoplastic/drug effects ; Breast Neoplasms/genetics ; Breast Neoplasms/drug therapy ; Breast Neoplasms/pathology ; Breast Neoplasms/metabolism ; Transcriptome/drug effects ; Gene Expression Profiling ; Signal Transduction/drug effects ; Apoptosis/drug effects ; Cell Membrane Permeability/drug effects ; Enzyme Inhibitors/pharmacology ; Triple Negative Breast Neoplasms/genetics ; Triple Negative Breast Neoplasms/drug therapy ; Triple Negative Breast Neoplasms/pathology ; Triple Negative Breast Neoplasms/metabolism
Chemical Substances	Protein Glutamine gamma Glutamyltransferase 2 (EC 2.3.2.13) ; Transglutaminases (EC 2.3.2.13) ; GTP-Binding Proteins (EC 3.6.1.-) ; Enzyme Inhibitors
Language	English
Publishing date	2024-04-10
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80229-3
ISSN	1089-8638 ; 0022-2836
ISSN (online)	1089-8638
ISSN	0022-2836
DOI	10.1016/j.jmb.2024.168569
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Zs.A 867: Show issues

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Jg. 1995 - 2021: Lesesall (1.OG)
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Article ; Online: Alzheimer and Purinergic Signaling: Just a Matter of Inflammation?

Merighi, Stefania / Poloni, Tino Emanuele / Terrazzan, Anna / Moretti, Eva / Gessi, Stefania / Ferrari, Davide

Cells

2021 Volume 10, Issue 5

Abstract: Alzheimer's disease (AD) is a widespread neurodegenerative pathology responsible for about 70% of all cases of dementia. Adenosine is an endogenous nucleoside that affects neurodegeneration by activating four membrane G protein-coupled receptor subtypes, ...

Abstract	Alzheimer's disease (AD) is a widespread neurodegenerative pathology responsible for about 70% of all cases of dementia. Adenosine is an endogenous nucleoside that affects neurodegeneration by activating four membrane G protein-coupled receptor subtypes, namely P1 receptors. One of them, the A
MeSH term(s)	Alzheimer Disease/etiology ; Alzheimer Disease/metabolism ; Alzheimer Disease/pathology ; Animals ; Humans ; Inflammation/physiopathology ; Purine Nucleotides/metabolism ; Receptors, Purinergic/metabolism
Chemical Substances	Purine Nucleotides ; Receptors, Purinergic
Language	English
Publishing date	2021-05-20
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells10051267
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Article ; Online: Circular RNAs Could Encode Unique Proteins and Affect Cancer Pathways

Crudele, Francesca / Bianchi, Nicoletta / Terrazzan, Anna / Ancona, Pietro / Frassoldati, Antonio / Gasparini, Paolo / D’Adamo, Adamo P. / Papaioannou, Dimitrios / Garzon, Ramiro / Wójcicka, Anna / Gaj, Paweł / Jażdżewski, Krystian / Palatini, Jeffrey / Volinia, Stefano

Biology (Basel). 2023 Mar. 24, v. 12, no. 4

2023

Abstract: circRNAs constitute a novel class of RNA, generally considered as non-coding RNAs; nonetheless, their coding potential has been under scrutiny. In this work, we systematically explored the predicted proteins of more than 160,000 circRNAs detected by ... ...

Abstract	circRNAs constitute a novel class of RNA, generally considered as non-coding RNAs; nonetheless, their coding potential has been under scrutiny. In this work, we systematically explored the predicted proteins of more than 160,000 circRNAs detected by exome capture RNA-sequencing and collected in the MiOncoCirc pan-cancer compendium, including normal and cancer samples from different types of tissues. For the functional evaluation, we compared their primary structure and domain composition with those derived from the same linear mRNAs. Among the 4362 circRNAs potentially encoding proteins with a unique primary structure and 1179 encoding proteins with a novel domain composition, 183 were differentially expressed in cancer. In particular, eight were associated with prognosis in acute myeloid leukemia. The functional classification of the dysregulated circRNA-encoded polypeptides showed an enrichment in the heme and cancer signaling, DNA-binding, and phosphorylation processes, and disclosed the roles of some circRNA-based effectors in cancer.
Keywords	RNA ; heme ; myeloid leukemia ; phosphorylation ; polypeptides ; prognosis ; sequence analysis
Language	English
Dates of publication	2023-0324
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article ; Online
ZDB-ID	2661517-4
ISSN	2079-7737
ISSN	2079-7737
DOI	10.3390/biology12040493
Database	NAL-Catalogue (AGRICOLA)

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Article: Circular RNAs Could Encode Unique Proteins and Affect Cancer Pathways.

Crudele, Francesca / Bianchi, Nicoletta / Terrazzan, Anna / Ancona, Pietro / Frassoldati, Antonio / Gasparini, Paolo / D'Adamo, Adamo P / Papaioannou, Dimitrios / Garzon, Ramiro / Wójcicka, Anna / Gaj, Paweł / Jażdżewski, Krystian / Palatini, Jeffrey / Volinia, Stefano

Biology

2023 Volume 12, Issue 4

Abstract	circRNAs constitute a novel class of RNA, generally considered as non-coding RNAs; nonetheless, their coding potential has been under scrutiny. In this work, we systematically explored the predicted proteins of more than 160,000 circRNAs detected by exome capture RNA-sequencing and collected in the MiOncoCirc pan-cancer compendium, including normal and cancer samples from different types of tissues. For the functional evaluation, we compared their primary structure and domain composition with those derived from the same linear mRNAs. Among the 4362 circRNAs potentially encoding proteins with a unique primary structure and 1179 encoding proteins with a novel domain composition, 183 were differentially expressed in cancer. In particular, eight were associated with prognosis in acute myeloid leukemia. The functional classification of the dysregulated circRNA-encoded polypeptides showed an enrichment in the heme and cancer signaling, DNA-binding, and phosphorylation processes, and disclosed the roles of some circRNA-based effectors in cancer.
Language	English
Publishing date	2023-03-24
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2661517-4
ISSN	2079-7737
ISSN	2079-7737
DOI	10.3390/biology12040493
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Article ; Online: Metabolic characterisation of transglutaminase 2 inhibitor effects in breast cancer cell lines.

Gallo, Mariana / Ferrari, Elena / Terrazzan, Anna / Brugnoli, Federica / Spisni, Alberto / Taccioli, Cristian / Aguiari, Gianluca / Trentini, Alessandro / Volinia, Stefano / Keillor, Jeffrey W / Bergamini, Carlo M / Bianchi, Nicoletta / Pertinhez, Thelma A

The FEBS journal

2023 Volume 290, Issue 22, Page(s) 5411–5433

Abstract: Transglutaminase 2 (TG2), which mediates post-translational modifications of multiple intracellular enzymes, is involved in the pathogenesis and progression of cancer. We ... ...

Abstract	Transglutaminase 2 (TG2), which mediates post-translational modifications of multiple intracellular enzymes, is involved in the pathogenesis and progression of cancer. We used
MeSH term(s)	Humans ; Female ; Protein Glutamine gamma Glutamyltransferase 2 ; Breast Neoplasms/metabolism ; MCF-7 Cells ; Apoptosis ; Metabolomics ; Cell Line, Tumor ; Transglutaminases/metabolism
Chemical Substances	Protein Glutamine gamma Glutamyltransferase 2 (EC 2.3.2.13) ; Transglutaminases (EC 2.3.2.13)
Language	English
Publishing date	2023-08-29
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2173655-8
ISSN	1742-4658 ; 1742-464X
ISSN (online)	1742-4658
ISSN	1742-464X
DOI	10.1111/febs.16931
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Zs.A 260: Show issues

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Article: The Molecular Networks of microRNAs and Their Targets in the Drug Resistance of Colon Carcinoma.

Crudele, Francesca / Bianchi, Nicoletta / Astolfi, Annalisa / Grassilli, Silvia / Brugnoli, Federica / Terrazzan, Anna / Bertagnolo, Valeria / Negrini, Massimo / Frassoldati, Antonio / Volinia, Stefano

Cancers

2021 Volume 13, Issue 17

Abstract: Drug resistance is one of the major forces driving a poor prognosis during the treatment and progression of human colon carcinomas. The molecular mechanisms that regulate the diverse processes underlying drug resistance are still under debate. MicroRNAs ( ...

Abstract	Drug resistance is one of the major forces driving a poor prognosis during the treatment and progression of human colon carcinomas. The molecular mechanisms that regulate the diverse processes underlying drug resistance are still under debate. MicroRNAs (miRNAs) are a subgroup of non-coding RNAs increasingly found to be associated with the regulation of tumorigenesis and drug resistance. We performed a systematic review of the articles concerning miRNAs and drug resistance in human colon cancer published from 2013 onwards in journals with an impact factor of 5 or higher. First, we built a network with the most studied miRNAs and targets (as nodes) while the drug resistance/s are indicated by the connections (edges); then, we discussed the most relevant miRNA/targets interactions regulated by drugs according to the network topology and statistics. Finally, we considered the drugs as nodes in the network, to allow an alternative point of view that could flow through the treatment options and the associated molecular pathways. A small number of microRNAs and proteins appeared as critically involved in the most common drugs used for the treatment of patients with colon cancer. In particular, the family of miR-200, miR34a, miR-155 and miR-17 appear as the most relevant microRNAs. Thus, regulating these miRNAs could be useful for interfering with some drug resistance mechanisms in colorectal carcinoma.
Language	English
Publishing date	2021-08-28
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers13174355
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