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The deubiquitinase ...
The deubiquitinase USP8 regulates ovarian cancer cell response to cisplatin by suppressing apoptosis
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- Corno, Cristina (author)
- Dept Expt Oncol, Italy
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- D´arcy, Padraig (author)
- Karolinska Institutet,Linköpings universitet,Avdelningen för klinisk kemi och farmakologi,Medicinska fakulteten
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- Bagnoli, Marina (author)
- Dept Expt Oncol, Italy
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- Paolini, Biagio (author)
- Fdn IRCCS Ist Nazl Tumori, Italy
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- Costantino, Matteo (author)
- Dept Expt Oncol, Italy
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- Carenini, Nives (author)
- Dept Expt Oncol, Italy
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- Corna, Elisabetta (author)
- Dept Expt Oncol, Italy
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- Alberti, Paola (author)
- Dept Expt Oncol, Italy
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- Mezzanzanica, Delia (author)
- Dept Expt Oncol, Italy
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- Colombo, Diego (author)
- Univ Milan, Italy
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- Linder, Stig (author)
- Linköpings universitet,Avdelningen för klinisk kemi och farmakologi,Medicinska fakulteten,Karolinska Inst, Sweden
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- Arrighetti, Noemi (author)
- Dept Expt Oncol, Italy
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- Perego, Paola (author)
- Dept Expt Oncol, Italy
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(creator_code:org_t)
- 2022-12-12
- 2022
- English.
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In: Frontiers in Cell and Developmental Biology. - : FRONTIERS MEDIA SA. - 2296-634X. ; 10
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https://liu.diva-por... (primary) (Raw object)
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https://urn.kb.se/re...
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https://doi.org/10.3...
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Abstract
Subject headings
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- The identification of therapeutic approaches to improve response to platinum-based therapies is an urgent need for ovarian carcinoma. Deubiquitinases are a large family of ubiquitin proteases implicated in a variety of cellular functions and may contribute to tumor aggressive features through regulation of processes such as proliferation and cell death. Among the subfamily of ubiquitin-specific peptidases, USP8 appears to be involved in modulation of cancer cell survival by still poorly understood mechanisms. Thus, we used ovarian carcinoma cells of different histotypes, including cisplatin-resistant variants with increased survival features to evaluate the efficacy of molecular targeting of USP8 as a strategy to overcome drug resistance/modulate cisplatin response. We performed biochemical analysis of USP8 activity in pairs of cisplatin-sensitive and -resistant cells and found increased USP8 activity in resistant cells. Silencing of USP8 resulted in decreased activation of receptor tyrosine kinases and increased sensitivity to cisplatin in IGROV-1/Pt1 resistant cells as shown by colony forming assay. Increased cisplatin sensitivity was associated with enhanced cisplatin-induced caspase 3/7 activation and apoptosis, a phenotype also observed in cisplatin sensitive cells. Increased apoptosis was linked to FLIPL decrease and cisplatin induction of caspase 3 in IGROV-1/Pt1 cells, cisplatin-induced claspin and survivin down-regulation in IGROV-1 cells, thereby showing a decrease of anti-apoptotic proteins. Immunohistochemical staining on 65 clinical specimens from advanced stage ovarian carcinoma indicated that 40% of tumors were USP8 positive suggesting that USP8 is an independent prognostic factor for adverse outcome when considering progression free survival as a clinical end-point. Taken together, our results support that USP8 may be of diagnostic value and may provide a therapeutic target to improve the efficacy of platinum-based therapy in ovarian carcinoma.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
Keyword
- ovarian cancer; ubiquitin-specific protease 8; cisplatin; drug resistance; apoptosis
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Corno, Cristina
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D´arcy, Padraig
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Bagnoli, Marina
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Paolini, Biagio
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Costantino, Matt ...
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Carenini, Nives
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Corna, Elisabett ...
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Alberti, Paola
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Mezzanzanica, De ...
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Colombo, Diego
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Linder, Stig
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Arrighetti, Noem ...
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Perego, Paola
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Cell and Molecul ...
- Articles in the publication
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Frontiers in Cel ...
- By the university
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Linköping University
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Karolinska Institutet