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Article ; Online: The Multifaceted Role of CMA in Glioma: Enemy or Ally?

Lo Dico, Alessia / Martelli, Cristina / Diceglie, Cecilia / Ottobrini, Luisa

International journal of molecular sciences

2021 Volume 22, Issue 4

Abstract: Chaperone-mediated autophagy (CMA) is a catabolic pathway fundamental for cell homeostasis, by which specific damaged or non-essential proteins are degraded. CMA activity has three main levels of regulation. The first regulatory level is based on the ... ...

Abstract	Chaperone-mediated autophagy (CMA) is a catabolic pathway fundamental for cell homeostasis, by which specific damaged or non-essential proteins are degraded. CMA activity has three main levels of regulation. The first regulatory level is based on the targetability of specific proteins possessing a KFERQ-like domain, which can be recognized by specific chaperones and delivered to the lysosomes. Target protein unfolding and translocation into the lysosomal lumen constitutes the second level of CMA regulation and is based on the modulation of Lamp2A multimerization. Finally, the activity of some accessory proteins represents the third regulatory level of CMA activity. CMA's role in oncology has not been fully clarified covering both pro-survival and pro-death roles in different contexts. Taking all this into account, it is possible to comprehend the actual complexity of both CMA regulation and the cellular consequences of its activity allowing it to be elected as a modulatory and not only catabolic machinery. In this review, the role covered by CMA in oncology is discussed with a focus on its relevance in glioma. Molecular correlates of CMA importance in glioma responsiveness to treatment are described to identify new early efficacy biomarkers and new therapeutic targets to overcome resistance.
MeSH term(s)	Antineoplastic Agents, Alkylating/pharmacology ; Chaperone-Mediated Autophagy/drug effects ; Chaperone-Mediated Autophagy/physiology ; Glioma/drug therapy ; Glioma/metabolism ; Glioma/pathology ; Humans ; Nuclear Proteins/metabolism ; Phosphoprotein Phosphatases/metabolism ; Proteins/metabolism ; Temozolomide/pharmacology
Chemical Substances	Antineoplastic Agents, Alkylating ; Nuclear Proteins ; Proteins ; PHLPP1 protein, human (EC 3.1.3.16) ; Phosphoprotein Phosphatases (EC 3.1.3.16) ; Temozolomide (YF1K15M17Y)
Language	English
Publishing date	2021-02-23
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms22042217
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Article ; Online: SARS-CoV-2 Vaccination Effectiveness in Rituximab-Treated Patients Affected by Pemphigus Vulgaris.

Fenizia, Claudio / Moltrasio, Chiara / Ottobrini, Luisa / Utyro, Olga / Genovese, Giovanni / Vanetti, Claudia / Trabattoni, Daria / Marzano, Angelo V

The Journal of investigative dermatology

2023 Volume 143, Issue 8, Page(s) 1601–1604

MeSH term(s)	Humans ; COVID-19/prevention & control ; COVID-19 Vaccines/administration & dosage ; Immunologic Factors ; Pemphigus/drug therapy ; Rituximab/adverse effects ; SARS-CoV-2 ; Vaccination
Chemical Substances	COVID-19 Vaccines ; Immunologic Factors ; Rituximab (4F4X42SYQ6)
Language	English
Publishing date	2023-01-28
Publishing country	United States
Document type	Journal Article
ZDB-ID	80136-7
ISSN	1523-1747 ; 0022-202X
ISSN (online)	1523-1747
ISSN	0022-202X
DOI	10.1016/j.jid.2022.12.023
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Article: Role of Metformin and AKT Axis Modulation in the Reversion of Hypoxia Induced TMZ-Resistance in Glioma Cells.

Lo Dico, Alessia / Valtorta, Silvia / Ottobrini, Luisa / Moresco, Rosa Maria

Frontiers in oncology

2019 Volume 9, Page(s) 463

Abstract: Hypoxia is a key driver of tumor adaptation promoting tumor progression and resistance to therapy. Hypoxia related pathways might represent attractive targets for the treatment of Glioblastoma Multiforme (GBM), that up to date is characterized by a poor ... ...

Abstract	Hypoxia is a key driver of tumor adaptation promoting tumor progression and resistance to therapy. Hypoxia related pathways might represent attractive targets for the treatment of Glioblastoma Multiforme (GBM), that up to date is characterized by a poor prognosis. Primary aim of this study was to investigate the role of hypoxia and hypoxia-related modifications in the effect of temozolomide (TMZ) given alone or in association with the antidiabetic agent Metformin (MET) or the PI3K/mTOR blocker, BEZ235. The study was conducted in the TMZ responsive U251 and resistant T98 GBM cells. Our results showed that during hypoxia, TMZ plus MET reduced viability of U251 cells affecting also CD133 and CD90 expressing cells. This effect was associated with a reduction of HIF-1α activity, VEGF release and AKT activation. In T98 TMZ-resistant cells, TMZ plus MET exerted similar effects on HIF-1α. However, in this cell line, TMZ plus MET failed to reduce CD133 positive cells and AKT phosphorylation. Nevertheless, the administration of the dual PI3K/mTOR inhibitor BEZ235 potentiated the effect of TMZ plus MET on cell viability, inducing a pro-apoptotic phenotype during hypoxic condition also in T98 cells, suggesting the block of the PI3K/AKT/mTOR pathway as a complementary target to further overcome GBM resistance during hypoxia. In conclusion, we proposed TMZ plus MET as suitable treatment to revert TMZ-resistance also during hypoxia, an effect potentiated by the inhibition of PI3K/mTOR axis.
Language	English
Publishing date	2019-05-31
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2019.00463
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Article ; Online: Triple negative aggressive phenotype controlled by miR-135b and miR-365: new theranostics candidates.

Bertoli, Gloria / Cava, Claudia / Corsi, Fabio / Piccotti, Francesca / Martelli, Cristina / Ottobrini, Luisa / Vaira, Valentina / Castiglioni, Isabella

Scientific reports

2021 Volume 11, Issue 1, Page(s) 6553

Abstract: Triple negative breast cancer (TNBC) accounts for about a fifth of all breast cancers and includes a diverse group of cancers. The heterogeneity of TNBC and the lack of target receptors on the cell surface make it difficult to develop specific ... ...

Abstract	Triple negative breast cancer (TNBC) accounts for about a fifth of all breast cancers and includes a diverse group of cancers. The heterogeneity of TNBC and the lack of target receptors on the cell surface make it difficult to develop specific therapeutic treatments. These aspects cause the high negative prognosis of patients with this type of tumor. The analysis of the molecular profiles of TNBC samples has allowed a better characterization of this tumor, supporting the search for new reliable diagnostic markers. To this end, we have developed a bioinformatic approach to integrate networks of genes differentially expressed in basal breast cancer compared to healthy tissues, with miRNAs able to regulate their expression. We studied the role of these miRNAs in TNBC subtype cell lines. We therefore identified two miRNAs, namely miR-135b and miR-365, with a central role in regulating the altered functional pathways in basal breast cancer. These two miRNAs are differentially expressed in human TNBC immunohistochemistry-selected tissues, and their modulation has been shown to play a role in the proliferation of tumor control and its migratory and invasive capacity in TNBC subtype cell lines. From the perspective of personalized medicine, we managed to modulate the expression of the two miRNAs in organotypic cultures, suggesting their possible use as diagnostic and therapeutic molecules. miR-135b and miR-365 have a key role in TNBC, controlling proliferation and invasion. Their detection could be helpful in TNBC diagnosis, while their modulation could become a new therapeutic tool for TNBC.
MeSH term(s)	Biomarkers, Tumor ; Cell Line, Tumor ; Cells, Cultured ; Female ; Gene Expression Regulation, Neoplastic ; Humans ; Immunohistochemistry ; Mesenchymal Stem Cells/metabolism ; MicroRNAs/genetics ; Molecular Targeted Therapy ; Phenotype ; Precision Medicine ; Triple Negative Breast Neoplasms/genetics ; Triple Negative Breast Neoplasms/pathology ; Triple Negative Breast Neoplasms/therapy
Chemical Substances	Biomarkers, Tumor ; MIRN135 microRNA, human ; MIRN365 microRNA, human ; MicroRNAs
Language	English
Publishing date	2021-03-22
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-021-85746-w
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Article ; Online: Theranostic application of

Cava, Claudia / Novello, Chiara / Martelli, Cristina / Lodico, Alessia / Ottobrini, Luisa / Piccotti, Francesca / Truffi, Marta / Corsi, Fabio / Bertoli, Gloria / Castiglioni, Isabella

Theranostics

2020 Volume 10, Issue 1, Page(s) 50–61

Abstract: Human epidermal growth factor receptor 2 (HER2) is overexpressed/amplified in one third of breast cancers (BCs), and is associated with the poorer prognosis and the higher metastatic potential in BC. Emerging evidences highlight the role of microRNAs ( ... ...

Abstract	Human epidermal growth factor receptor 2 (HER2) is overexpressed/amplified in one third of breast cancers (BCs), and is associated with the poorer prognosis and the higher metastatic potential in BC. Emerging evidences highlight the role of microRNAs (miRNAs) in the regulation of several cellular processes, including BC. Methods: Here we identified, by Results: We found that their expression is dysregulated in both HER2+ BC cell lines and human samples. Focusing our study on the only upregulated miRNA, Conclusions: In HER2+ BC oncogenic
MeSH term(s)	Animals ; Biomarkers, Tumor/metabolism ; Breast Neoplasms/metabolism ; Cell Line, Tumor ; Cell Movement ; Cell Proliferation ; Female ; Gene Expression Regulation, Neoplastic ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Mice ; Mice, Nude ; MicroRNAs/metabolism ; Receptor, ErbB-2/metabolism ; Theranostic Nanomedicine
Chemical Substances	Biomarkers, Tumor ; HIF1A protein, human ; Hypoxia-Inducible Factor 1, alpha Subunit ; MIRN429 microRNA, human ; MicroRNAs ; ERBB2 protein, human (EC 2.7.10.1) ; Receptor, ErbB-2 (EC 2.7.10.1)
Language	English
Publishing date	2020-01-01
Publishing country	Australia
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2592097-2
ISSN	1838-7640 ; 1838-7640
ISSN (online)	1838-7640
ISSN	1838-7640
DOI	10.7150/thno.36274
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Article: Hypoxia-Inducible Factor-1α Activity as a Switch for Glioblastoma Responsiveness to Temozolomide.

Lo Dico, Alessia / Martelli, Cristina / Diceglie, Cecilia / Lucignani, Giovanni / Ottobrini, Luisa

Frontiers in oncology

2018 Volume 8, Page(s) 249

Abstract: Rationale: The activity of the transcription factor, hypoxia-inducible factor (HIF)-1α, is a common driver of a number of the pathways involved in the aggressiveness of glioblastomas (GBMs), and it has been suggested that the reduction in this activity ... ...

Abstract	Rationale: The activity of the transcription factor, hypoxia-inducible factor (HIF)-1α, is a common driver of a number of the pathways involved in the aggressiveness of glioblastomas (GBMs), and it has been suggested that the reduction in this activity observed, soon after the administration of temozolomide (TMZ), can be a biomarker of an early response in GBM models. As HIF-1α is a tightly regulated protein, studying the processes involved in its downregulation could shed new light on the mechanisms underlying GBM sensitivity or resistance to TMZ. Methods: The effect of HIF-1α silencing on cell responsiveness to TMZ was assessed in four genetically different human GBM cell lines by evaluating cell viability and apoptosis-related gene balance. LAMP-2A silencing was used to evaluate the contribution of chaperone-mediated autophagy (CMA) to the modulation of HIF-1α activity in TMZ-sensitive and TMZ-resistant cells. Results: The results showed that HIF-1α but not HIF-2α activity is associated with GBM responsiveness to TMZ: its downregulation improves the response of TMZ-resistant cells, while blocking CMA-mediated HIF-1α degradation induces resistance to TMZ in TMZ-sensitive cells. These findings are in line with the modulation of crucial apoptosis-related genes. Conclusion: Our results demonstrate the central role played by HIF-1α activity in determining the sensitivity or resistance of GBMs to TMZ, and we suggest that CMA is the cellular mechanism responsible for modulating this activity after TMZ treatment.
Language	English
Publishing date	2018-07-02
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2018.00249
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Article ; Online: Transcriptional activity of oestrogen receptors in the course of embryo development.

Della Torre, Sara / Rando, Gianpaolo / Meda, Clara / Ciana, Paolo / Ottobrini, Luisa / Maggi, Adriana

The Journal of endocrinology

2018 Volume 238, Issue 3, Page(s) 165–176

Abstract: Oestrogens are well-known proliferation and differentiation factors that play an essential role in the correct development of sex-related organs and behaviour in mammals. With the use of the ERE-Luc reporter mouse model, we show herein that throughout ... ...

Abstract	Oestrogens are well-known proliferation and differentiation factors that play an essential role in the correct development of sex-related organs and behaviour in mammals. With the use of the ERE-Luc reporter mouse model, we show herein that throughout mouse development, oestrogen receptors (ERs) are active starting from day 12 post conception. Most interestingly, we show that prenatal luciferase expression in each organ is proportionally different in relation to the germ layer of the origin. The luciferase content is highest in ectoderm-derived organs (such as brain and skin) and is lowest in endoderm-derived organs (such as liver, lung, thymus and intestine). Consistent with the testosterone surge occurring in male mice at the end of pregnancy, in the first 2 days after birth, we observed a significant increase in the luciferase content in several organs, including the liver, bone, gonads and hindbrain. The results of the present study show a widespread transcriptional activity of ERs in developing embryos, pointing to the potential contribution of these receptors in the development of non-reproductive as well as reproductive organs. Consequently, the findings reported here might be relevant in explaining the significant differences in male and female physiopathology reported by a growing number of studies and may underline the necessity for more systematic analyses aimed at the identification of the prenatal effects of drugs interfering with ER signalling, such as aromatase inhibitors or endocrine disrupter chemicals.
MeSH term(s)	Animals ; Embryo, Mammalian ; Embryonic Development/drug effects ; Embryonic Development/genetics ; Estrogens/pharmacology ; Female ; Fulvestrant/pharmacology ; Gene Expression Regulation, Developmental/drug effects ; Genes, Reporter/drug effects ; Luciferases/genetics ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Pregnancy ; Receptors, Estrogen/antagonists & inhibitors ; Receptors, Estrogen/metabolism ; Receptors, Estrogen/physiology ; Response Elements/drug effects ; Response Elements/genetics ; Transcriptional Activation/drug effects ; Transcriptional Activation/genetics
Chemical Substances	Estrogens ; Receptors, Estrogen ; Fulvestrant (22X328QOC4) ; Luciferases (EC 1.13.12.-)
Language	English
Publishing date	2018-07-16
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3028-4
ISSN	1479-6805 ; 0022-0795
ISSN (online)	1479-6805
ISSN	0022-0795
DOI	10.1530/JOE-18-0003
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Article ; Online: Intracellular Redox-Balance Involvement in Temozolomide Resistance-Related Molecular Mechanisms in Glioblastoma.

Lo Dico, Alessia / Salvatore, Daniela / Martelli, Cristina / Ronchi, Dario / Diceglie, Cecilia / Lucignani, Giovanni / Ottobrini, Luisa

Cells

2019 Volume 8, Issue 11

Abstract: Glioblastoma (GBM) is the most common astrocytic-derived brain tumor in adults, characterized by a poor prognosis mainly due to the resistance to the available therapy. The study of mitochondria-derived oxidative stress, and of the biological events that ...

Abstract	Glioblastoma (GBM) is the most common astrocytic-derived brain tumor in adults, characterized by a poor prognosis mainly due to the resistance to the available therapy. The study of mitochondria-derived oxidative stress, and of the biological events that orbit around it, might help in the comprehension of the molecular mechanisms at the base of GBM responsiveness to Temozolomide (TMZ). Sensitive and resistant GBM cells were used to test the role of mitochondrial ROS release in TMZ-resistance. Chaperone-Mediated Autophagy (CMA) activation in relation to reactive oxygen species (ROS) release has been measured by monitoring the expression of specific genes. Treatments with H
MeSH term(s)	Apoptosis ; Autophagy/drug effects ; Autophagy/physiology ; Brain Neoplasms/genetics ; Cell Line, Tumor ; Chaperone-Mediated Autophagy/drug effects ; Chaperone-Mediated Autophagy/physiology ; Cytoplasm/metabolism ; Drug Resistance, Neoplasm/genetics ; Glioblastoma/drug therapy ; Glioblastoma/metabolism ; Humans ; Hydrogen Peroxide ; Mitochondria/metabolism ; Oxidation-Reduction ; Oxidative Stress/physiology ; Reactive Oxygen Species/metabolism ; Signal Transduction ; Temozolomide/metabolism ; Temozolomide/pharmacology
Chemical Substances	Reactive Oxygen Species ; Hydrogen Peroxide (BBX060AN9V) ; Temozolomide (YF1K15M17Y)
Language	English
Publishing date	2019-10-24
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells8111315
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Article ; Online: Placental Antioxidant Defenses and Autophagy-Related Genes in Maternal Obesity and Gestational Diabetes Mellitus.

Diceglie, Cecilia / Anelli, Gaia Maria / Martelli, Cristina / Serati, Anais / Lo Dico, Alessia / Lisso, Fabrizia / Parisi, Francesca / Novielli, Chiara / Paleari, Renata / Cetin, Irene / Ottobrini, Luisa / Mandò, Chiara

Nutrients

2021 Volume 13, Issue 4

Abstract: Maternal obesity and gestational diabetes mellitus (GDM) are increasing worldwide, representing risk factors for both mother and child short/long-term outcomes. Oxidative stress, lipotoxicity and altered autophagy have already been reported in obesity, ... ...

Abstract	Maternal obesity and gestational diabetes mellitus (GDM) are increasing worldwide, representing risk factors for both mother and child short/long-term outcomes. Oxidative stress, lipotoxicity and altered autophagy have already been reported in obesity, but few studies have focused on obese pregnant women with GDM. Antioxidant and macro/chaperone-mediated autophagy (CMA)-related gene expressions were evaluated herein in obese and GDM placentas. A total of 47 women with singleton pregnancies delivered by elective cesarean section were enrolled: 16 normal weight (NW), 18 obese with no comorbidities (OB GDM(-)), 13 obese with GDM (OB GDM(+)). Placental gene expression was assessed by real-time PCR. Antioxidant gene expression (
MeSH term(s)	Adult ; Antioxidants/metabolism ; Autophagy/genetics ; Cesarean Section ; Diabetes, Gestational/genetics ; Female ; Humans ; Obesity, Maternal/genetics ; Oxidative Stress/genetics ; Placenta/metabolism ; Pregnancy
Chemical Substances	Antioxidants
Language	English
Publishing date	2021-04-15
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2518386-2
ISSN	2072-6643 ; 2072-6643
ISSN (online)	2072-6643
ISSN	2072-6643
DOI	10.3390/nu13041303
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Article ; Online: Optical imaging probes in oncology.

Martelli, Cristina / Lo Dico, Alessia / Diceglie, Cecilia / Lucignani, Giovanni / Ottobrini, Luisa

Oncotarget

2016 Volume 7, Issue 30, Page(s) 48753–48787

Abstract: Cancer is a complex disease, characterized by alteration of different physiological molecular processes and cellular features. Keeping this in mind, the possibility of early identification and detection of specific tumor biomarkers by non-invasive ... ...

Abstract	Cancer is a complex disease, characterized by alteration of different physiological molecular processes and cellular features. Keeping this in mind, the possibility of early identification and detection of specific tumor biomarkers by non-invasive approaches could improve early diagnosis and patient management.Different molecular imaging procedures provide powerful tools for detection and non-invasive characterization of oncological lesions. Clinical studies are mainly based on the use of computed tomography, nuclear-based imaging techniques and magnetic resonance imaging. Preclinical imaging in small animal models entails the use of dedicated instruments, and beyond the already cited imaging techniques, it includes also optical imaging studies. Optical imaging strategies are based on the use of luminescent or fluorescent reporter genes or injectable fluorescent or luminescent probes that provide the possibility to study tumor features even by means of fluorescence and luminescence imaging. Currently, most of these probes are used only in animal models, but the possibility of applying some of them also in the clinics is under evaluation.The importance of tumor imaging, the ease of use of optical imaging instruments, the commercial availability of a wide range of probes as well as the continuous description of newly developed probes, demonstrate the significance of these applications. The aim of this review is providing a complete description of the possible optical imaging procedures available for the non-invasive assessment of tumor features in oncological murine models. In particular, the characteristics of both commercially available and newly developed probes will be outlined and discussed.
MeSH term(s)	Animals ; Biomarkers, Tumor/metabolism ; Early Detection of Cancer/methods ; Fluorescent Dyes/administration & dosage ; Genes, Reporter/genetics ; Humans ; Luminescent Measurements/methods ; Magnetic Resonance Imaging/methods ; Molecular Imaging/methods ; Neoplasms/diagnostic imaging ; Neoplasms/metabolism ; Neoplasms/pathology ; Neoplasms, Experimental/diagnostic imaging ; Optical Imaging/instrumentation ; Optical Imaging/methods ; Sensitivity and Specificity ; Staining and Labeling/methods
Chemical Substances	Biomarkers, Tumor ; Fluorescent Dyes
Language	English
Publishing date	2016-04-29
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2560162-3
ISSN	1949-2553 ; 1949-2553
ISSN (online)	1949-2553
ISSN	1949-2553
DOI	10.18632/oncotarget.9066
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