ROSSELLA BENEDETTI

Dottoressa di ricerca

ciclo: XXXVI



Titolo della tesi: Unfolded Protein Response manipulation in cancer treatment

Cancer cells are exposed to intrinsic and extrinsic factors that alter the homeostasis of the endoplasmic reticulum (ER), resulting in constitutive ER stress. To adapt to this stress, cancer cells activate the unfolded protein response (UPR), which usually sustains their survival. However, the activation of UPR can be considered a "double-edged sword", as it may also trigger cell death, i.e. in conditions of too long or intense stress. Approaches based on the manipulation of UPR are emerging as promising strategies for the treatment of cancer, either alone or in combination with existing drugs. In this study, we shed more light on the molecular mechanisms underlying the effects of UPR targeting by using natural compounds, such as Resveratrol, Curcumin, and DPE, or drugs that specifically alter ER homeostasis, such as Thapsigargin and Tunicamycin. By pharmacologic and genetic strategies, we observed that the UPR sensors, IRE1α, PERK, and ATF6, have different, and sometimes opposite, roles in balancing death/survival in stressed cells, also depending on the cellular context and the genetic background. For example, while the inhibition of ATF6 was the most effective in decreasing the survival of colon cancer cells undergoing ER stress, the inhibition of IRE1α was the most promising strategy, both in vitro and in vivo, for the treatment of B-cell lymphomas. Furthermore, in agreement with previous studies, we evidenced the close relationship between the UPR and other adaptive responses, such as autophagy and DNA damage response (DDR), influencing the resistance to anti-tumor treatments. In this regard, we described for the first time the role of ATF6 in protecting cells from cell death and DNA damage by sustaining the expression of BRCA1 in TG- or DPE-treated cells. Moreover, we evidenced a new role of ATF6 in supporting lysosomal function, thus directly linking UPR to autophagy. The latter process, together with chaperone mediated autophagy (CMA) were activated by ER stress and contributed to the degradation of mutp53 protein, with important implications for anti-cancer therapy. From these studies, it emerges that UPR and its dynamic interplay with other adaptive responses may be manipulated with important consequences in term of death/survival of stressed cancer cells and that the outcome may be dependent on the cellular context.

Produzione scientifica

11573/1696204 - 2023 - NFE2L2 and STAT3 converge on common targets to promote survival of primary lymphoma cells
Arena, Andrea; Di Crosta, Michele; Gonnella, Roberta; Zarrella, Roberta; Romeo, Maria Anele; Benedetti, Rossella; Gilardini Montani, Maria Saveria; Santarelli, Roberta; D’Orazi, Gabriella; Cirone, Mara - 01a Articolo in rivista
rivista: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (Basel (Matthaeustrasse 11) : Molecular Diversity Preservation International MDPI) pp. - - issn: 1661-6596 - wos: WOS:001036167700001 (1) - scopus: 2-s2.0-85166018355 (1)

11573/1696270 - 2023 - JQ-1/bortezomib combination strongly impairs MM and PEL survival by inhibiting c-Myc and mTOR despite the activation of prosurvival mechanisms
Arena, Andrea; Romeo, Maria Anele; Benedetti, Rossella; Gilardini Montani, Maria Saveria; Cirone, Mara - 01a Articolo in rivista
rivista: EXPERIMENTAL HEMATOLOGY (Elsevier Science Incorporated / NY Journals:Madison Square Station, PO Box 882:New York, NY 10159:(212)633-3730, EMAIL: usinfo-f@elsevier.com, INTERNET: http://www.elsevier.com, Fax: (212)633-3680) pp. 28-41 - issn: 0301-472X - wos: WOS:000957826000001 (2) - scopus: 2-s2.0-85147270519 (2)

11573/1696290 - 2023 - NRF2 and STAT3: friends or foes in carcinogenesis?
Arena, Andrea; Romeo, Maria Anele; Benedetti, Rossella; Gilardini Montani, Maria Saveria; Santarelli, Roberta; Gonnella, Roberta; D'orazi, Gabriella; Cirone, Mara - 01g Articolo di rassegna (Review)
rivista: DISCOVER ONCOLOGY ([New York]: Springer, 2021-) pp. 37- - issn: 2730-6011 - wos: WOS:000961857300002 (4) - scopus: 2-s2.0-85153108305 (4)

11573/1671685 - 2023 - Different outcome of targeting ERN1/IRE1 alpha and EIF2AK3/PERK in NSG mice engrafted with primary effusion lymphoma
Arena, Andrea; Romeo, Maria Anele; Focaccetti, Chiara; Anastasiadou, Eleni; Trivedi, Pankaj; Cifaldi, Loredana; Gilardini Montani, Maria Saveria; Benedetti, Rossella; Santarelli, Roberta; Gonnella, Roberta; Benvenuto, Monica; Marchese, Cinzia; Masuelli, Laura; Bei, Roberto; Cirone, Mara - 01f Lettera, Nota
rivista: BRITISH JOURNAL OF HAEMATOLOGY (Oxford]: [Blackwell Science].) pp. 1-4 - issn: 1365-2141 - wos: WOS:000935692900001 (1) - scopus: 2-s2.0-85148023663 (1)

11573/1691548 - 2023 - The inhibition of IRE1alpha/XBP1 axis prevents EBV-driven lymphomagenesis in NSG mice
Arena, Andrea; Romeo, Maria Anele; Po, Agnese; Benedetti, Rossella; Gilardini Montani, Maria Saveria; Gonnella, Roberta; Santarelli, Roberta; Gaeta, Aurelia; De Smaele, Enrico; Cirone, Mara - 01a Articolo in rivista
rivista: MICROBIOLOGY SPECTRUM (Washington, DC : ASM Press, 2014-) pp. 1-6 - issn: 2165-0497 - wos: WOS:001095474200001 (0) - scopus: 2-s2.0-85180012834 (0)

11573/1696211 - 2023 - HSP110 Inhibition in Primary Effusion Lymphoma Cells. One Molecule, Many Pro-Survival Targets
Gonnella, Roberta; Zarrella, Roberta; Di Crosta, Michele; Benedetti, Rossella; Arena, Andrea; Santarelli, Roberta; Gilardini Montani, Maria Saveria; D’Orazi, Gabriella; Cirone, Mara - 01a Articolo in rivista
rivista: CANCERS (Basel: MDPI) pp. 1-12 - issn: 2072-6694 - wos: WOS:001115967900001 (0) - scopus: 2-s2.0-85178926403 (0)

11573/1696294 - 2023 - Acetylation increases expression, interaction with TRAPPC4 and surface localization of PD-L1
Romeo, Maria Anele; Gilardini Montani, Maria Saveria; Santarelli, Roberta; Benedetti, Rossella; Arena, Andrea; Cirone, Mara - 01a Articolo in rivista
rivista: DISCOVER ONCOLOGY ([New York]: Springer, 2021-) pp. 152- - issn: 2730-6011 - wos: WOS:001052800600002 (1) - scopus: 2-s2.0-85168487188 (1)

11573/1587456 - 2022 - DNA damage triggers an interplay between wtp53 and c-Myc affecting lymphoma cell proliferation and Kaposi sarcoma herpesvirus replication
Arena, A.; Gilardini Montani, M. S.; Romeo, M. A.; Benedetti, R.; Gaeta, A.; Cirone, M. - 01a Articolo in rivista
rivista: BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH (Elsevier BV:PO Box 211, 1000 AE Amsterdam Netherlands:011 31 20 4853757, 011 31 20 4853642, 011 31 20 4853641, EMAIL: nlinfo-f@elsevier.nl, INTERNET: http://www.elsevier.nl, Fax: 011 31 20 4853598) pp. 1-11 - issn: 0167-4889 - wos: WOS:000717326400005 (16) - scopus: 2-s2.0-85118539605 (16)

11573/1640499 - 2022 - Targeting c-Myc Unbalances UPR towards Cell Death and Impairs DDR in Lymphoma and Multiple Myeloma Cells
Arena, A.; Romeo, M. A.; Benedetti, R.; Gilardini Montani, M. S.; Cirone, M. - 01a Articolo in rivista
rivista: BIOMEDICINES (Basel : MDPI) pp. 1-12 - issn: 2227-9059 - wos: WOS:000786755100001 (9) - scopus: 2-s2.0-85127699313 (9)

11573/1640511 - 2022 - The impairment of DDR reduces XBP1s, further increasing DNA damage, and triggers autophagy via PERK/eIF2alpha in MM and IRE1alpha/JNK1/2 in PEL cells
Arena, A.; Romeo, M. A.; Benedetti, R.; Gilardini Montani, M. S.; Cirone, M. - 01a Articolo in rivista
rivista: BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS (San Diego [etc.]: Elsevier [etc.]) pp. 19-25 - issn: 0006-291X - wos: WOS:000878132700004 (2) - scopus: 2-s2.0-85129320111 (3)

11573/1659741 - 2022 - Concomitant Inhibition of IRE1α/XBP1 Axis of UPR and PARP. A Promising Therapeutic Approach against c-Myc and Gammaherpesvirus-Driven B-Cell Lymphomas
Benedetti, R.; Arena, A.; Romeo, M. A.; Gilardini Montani, M. S.; Gonnella, R.; Santarelli, R.; Trivedi, P.; Cirone, M. - 01a Articolo in rivista
rivista: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (Basel (Matthaeustrasse 11) : Molecular Diversity Preservation International MDPI) pp. 1-13 - issn: 1661-6596 - wos: WOS:000846661400001 (3) - scopus: 2-s2.0-85137722317 (4)

11573/1671667 - 2022 - ATF6 prevents DNA damage and cell death in colon cancer cells undergoing ER stress
Benedetti, Rossella; Romeo, Maria Anele; Arena, Andrea; Gilardini Montani, Maria Saveria; Di Renzo, Livia; D'orazi, Gabriella; Cirone, Mara - 01a Articolo in rivista
rivista: CELL DEATH DISCOVERY ([London]: Nature Publishing Group, 2015-) pp. 1-12 - issn: 2058-7716 - wos: WOS:000815638500001 (9) - scopus: 2-s2.0-85132944532 (12)

11573/1640535 - 2022 - p62/SQSTM1 promotes mitophagy and activates the NRF2-mediated antioxidant and anti-inflammatory response restraining EBV-driven B lymphocyte proliferation
Gilardini Montani, Maria Saveria; Tarquini, Greta; Santarelli, Roberta; Gonnella, Roberta; Romeo, Maria Anele; Benedetti, Rossella; Arena, Andrea; Faggioni, Alberto; Cirone, Mara - 01a Articolo in rivista
rivista: CARCINOGENESIS (Oxford University Press:Journals Department, Great Clarendon Street, Oxford OX2 6DP United Kingdom:011 44 1865 556767, EMAIL: jnlorders@oup.co.uk, INTERNET: http://www.oup.co.uk, Fax: 011 44 1865 267485) pp. 277-287 - issn: 0143-3334 - wos: WOS:000756810200001 (11) - scopus: 2-s2.0-85129269602 (12)

11573/1614983 - 2022 - VPA and TSA Interrupt the Interplay between mutp53 and HSP70, Leading to CHK1 and RAD51 Down-Regulation and Sensitizing Pancreatic Cancer Cells to AZD2461 PARP Inhibitor
Romeo, M. A.; Gilardini Montani, M. S.; Benedetti, R.; Arena, A.; D'orazi, G.; Cirone, M. - 01a Articolo in rivista
rivista: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (Basel (Matthaeustrasse 11) : Molecular Diversity Preservation International MDPI) pp. 1-14 - issn: 1661-6596 - wos: WOS:000772044700001 (11) - scopus: 2-s2.0-85124907434 (12)

11573/1627726 - 2022 - The dysregulation of autophagy and ER stress induced by HHV-6A infection activates pro-inflammatory pathways and promotes the release of inflammatory cytokines and cathepsin S by CNS cells
Romeo, M. A.; Gilardini Montani, M. S.; Benedetti, R.; Arena, A.; Gaeta, A.; Cirone, M. - 01a Articolo in rivista
rivista: VIRUS RESEARCH (Elsevier BV:PO Box 211, 1000 AE Amsterdam Netherlands:011 31 20 4853757, 011 31 20 4853642, 011 31 20 4853641, EMAIL: nlinfo-f@elsevier.nl, INTERNET: http://www.elsevier.nl, Fax: 011 31 20 4853598) pp. 1-9 - issn: 0168-1702 - wos: WOS:000777670800001 (2) - scopus: 2-s2.0-85125851175 (2)

11573/1659739 - 2022 - c-Myc Sustains Pancreatic Cancer Cell Survival and mutp53 Stability through the Mevalonate Pathway
Romeo, Maria Anele; Gilardini Montani, Maria Saveria; Arena, Andrea; Benedetti, Rossella; D’Orazi, Gabriella; Cirone, Mara - 01a Articolo in rivista
rivista: BIOMEDICINES (Basel : MDPI) pp. 1-13 - issn: 2227-9059 - wos: WOS:000872167900001 (1) - scopus: 2-s2.0-85140649876 (1)

11573/1587474 - 2021 - New insights into curcumin-and resveratrol-mediated anti-cancer effects
Arena, A.; Romeo, M. A.; Benedetti, R.; Masuelli, L.; Bei, R.; Gilardini Montani, M. S.; Cirone, M. - 01a Articolo in rivista
rivista: PHARMACEUTICALS (Basel : MDPI, Molecular Diversity Preservation International, 2004-) pp. 1-12 - issn: 1424-8247 - wos: WOS:000727825100001 (25) - scopus: 2-s2.0-85117921973 (29)

11573/1577796 - 2021 - Role of upr sensor activation in cell death–survival decision of colon cancer cells stressed by dpe treatment
Benedetti, R.; Gilardini Montani, M. S.; Romeo, M. A.; Arena, A.; Santarelli, R.; D'orazi, G.; Cirone, M. - 01a Articolo in rivista
rivista: BIOMEDICINES (Basel : MDPI) pp. 1-14 - issn: 2227-9059 - wos: WOS:000699083100001 (11) - scopus: 2-s2.0-85115785094 (11)

11573/1551365 - 2021 - PGE2 released by pancreatic cancer cells undergoing ER stress transfers the stress to DCs impairing their immune function
Gilardini Montani, M. S.; Benedetti, R.; Piconese, S.; Pulcinelli, F. M.; Timperio, A. M.; Romeo, M. A.; Masuelli, L.; Mattei, M.; Bei, R.; D'orazi, G.; Cirone, M. - 01a Articolo in rivista
rivista: MOLECULAR CANCER THERAPEUTICS (Philadelphia, PA : American Association for Cancer Research, c2001-) pp. 934-945 - issn: 1535-7163 - wos: WOS:000648517900015 (14) - scopus: 2-s2.0-85105258016 (13)

11573/1542820 - 2021 - p53-R273H Sustains ROS, Pro-Inflammatory Cytokine Release and mTOR Activation While Reducing Autophagy, Mitophagy and UCP2 Expression, Effects Prevented by wtp53
Romeo, M. A.; Gilardini Montani, M. S.; Benedetti, R.; Arena, A.; D'orazi, G.; Cirone, M. - 01a Articolo in rivista
rivista: BIOMOLECULES (Basel: MDPI) pp. 1-14 - issn: 2218-273X - wos: WOS:000633432800001 (6) - scopus: 2-s2.0-85101254797 (4)

11573/1581319 - 2021 - Anticancer effect of AZD2461 PARP inhibitor against colon cancer cells carrying wt or dysfunctional p53
Romeo, M. A.; Gilardini Montani, M. S.; Benedetti, R.; Arena, A.; Maretto, M.; Bassetti, E.; Caiazzo, R.; D'orazi, G.; Cirone, M. - 01a Articolo in rivista
rivista: EXPERIMENTAL CELL RESEARCH (Academic Press Incorporated:6277 Sea Harbor Drive:Orlando, FL 32887:(800)543-9534, (407)345-4100, EMAIL: ap@acad.com, INTERNET: http://www.idealibrary.com, Fax: (407)352-3445) pp. 1-9 - issn: 0014-4827 - wos: WOS:000708776900014 (10) - scopus: 2-s2.0-85116884973 (9)

11573/1542828 - 2021 - The cross-talk between STAT1/STAT3 and ROS up-regulates PD-L1 and promotes the release of pro-inflammatory/immune suppressive cytokines in primary monocytes infected by HHV-6B
Romeo, M. A.; Gilardini Montani, M. S.; Benedetti, R.; Giambelli, L.; D'aprile, R.; Gaeta, A.; Faggioni, A.; Cirone, M. - 01a Articolo in rivista
rivista: VIRUS RESEARCH (Elsevier BV:PO Box 211, 1000 AE Amsterdam Netherlands:011 31 20 4853757, 011 31 20 4853642, 011 31 20 4853641, EMAIL: nlinfo-f@elsevier.nl, INTERNET: http://www.elsevier.nl, Fax: 011 31 20 4853598) pp. 1-6 - issn: 0168-1702 - wos: WOS:000604213400010 (12) - scopus: 2-s2.0-85097384111 (12)

11573/1410107 - 2020 - PBA preferentially impairs cell survival of glioblastomas carrying mutp53 by reducing its expression level, stabilizing wtp53, downregulating the mevalonate kinase and dysregulating UPR
Romeo, M. A.; Gilardini Montani, M. S.; Benedetti, R.; Garufi, A.; D'orazi, G.; Cirone, M. - 01a Articolo in rivista
rivista: BIOMOLECULES (Basel: MDPI) pp. 1-11 - issn: 2218-273X - wos: WOS:000539492400092 (4) - scopus: 2-s2.0-85083418218 (4)

11573/1447617 - 2020 - STAT3 and mutp53 Engage a Positive Feedback Loop Involving HSP90 and the Mevalonate Pathway
Romeo, M. A.; Gilardini Montani, M. S.; Benedetti, R.; Santarelli, R.; D'orazi, G.; Cirone, M. - 01a Articolo in rivista
rivista: FRONTIERS IN ONCOLOGY (Lausanne : Frontiers Editorial Office, 2011-) pp. 1-11 - issn: 2234-943X - wos: WOS:000555932000001 (21) - scopus: 2-s2.0-85088513415 (21)

11573/1546732 - 2020 - Viral Infection and Autophagy Dysregulation. The Case of HHV-6, EBV and KSHV
Romeo, M. A.; Santarelli, R.; Gilardini Montani, M. S.; Gonnella, R.; Benedetti, R.; Faggioni, A.; Cirone, M. - 01g Articolo di rassegna (Review)
rivista: CELLS (Basel: mdpi-Molecular Diversity Preservation International) pp. 1-8 - issn: 2073-4409 - wos: WOS:000601802000001 (6) - scopus: 2-s2.0-85097915798 (9)

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