Evaluating Targeted Therapies in Ovarian Cancer Metabolism : Novel Role for PCSK9 and Second Generation mTOR Inhibitors

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dc.contributor.author Sanz, Dafne Jacome
dc.contributor.author Raivola, Juuli
dc.contributor.author Karvonen, Hanna
dc.contributor.author Arjama, Mariliina
dc.contributor.author Barker, Harlan
dc.contributor.author Murumägi, Astrid
dc.contributor.author Ungureanu, Daniela
dc.date.accessioned 2021-09-17T11:30:01Z
dc.date.available 2021-09-17T11:30:01Z
dc.date.issued 2021-08
dc.identifier.citation Sanz , D J , Raivola , J , Karvonen , H , Arjama , M , Barker , H , Murumägi , A & Ungureanu , D 2021 , ' Evaluating Targeted Therapies in Ovarian Cancer Metabolism : Novel Role for PCSK9 and Second Generation mTOR Inhibitors ' , Cancers , vol. 13 , no. 15 , 3727 . https://doi.org/10.3390/cancers13153727
dc.identifier.other PURE: 168543041
dc.identifier.other PURE UUID: 1785bac1-ce17-49df-9a18-3a2b5f36befd
dc.identifier.other WOS: 000681959300001
dc.identifier.other ORCID: /0000-0003-1627-9571/work/100132427
dc.identifier.other ORCID: /0000-0002-9314-4972/work/100132566
dc.identifier.uri http://hdl.handle.net/10138/334436
dc.description.abstract Simple Summary Ovarian cancer (OC) is known for its poor prognosis, due to the absence of reliable biomarkers and its late diagnosis, since the early-stage disease is almost asymptomatic. Lipid metabolism plays an important role in OC progression due to the development of omental metastasis in the abdominal cavity. The aim of our study was to assess the therapeutic role of various enzymes involved in lipid metabolism regulation or synthesis, in different subtypes of OC represented by cell lines as well as patient-derived cancer cell cultures (PDCs). We show that proprotein convertase subtilisin/kexin type 9 (PCSK9), a cholesterol-regulating enzyme, plays a pro-survival role in OC and targeting its expression impairs cancer cell growth. We also tested a small library of metabolic and mTOR-targeting drugs to identify drug vulnerabilities specific to various subtypes of OC. Our results show that in OC cell lines and PDCs the second generation of mTOR inhibitors such as AZD8055, vistusertib, dactolisib and sapanisertib, have higher cytotoxic activity compared to the first generation mTOR inhibitors such as rapalogs. These results suggest that, in the era of precision medicine, it is possible to target the metabolic pathway in OC and identify subtype-specific drug vulnerabilities that could be advanced to the clinic. Background: Dysregulated lipid metabolism is emerging as a hallmark in several malignancies, including ovarian cancer (OC). Specifically, metastatic OC is highly dependent on lipid-rich omentum. We aimed to investigate the therapeutic value of targeting lipid metabolism in OC. For this purpose, we studied the role of PCSK9, a cholesterol-regulating enzyme, in OC cell survival and its downstream signaling. We also investigated the cytotoxic efficacy of a small library of metabolic (n = 11) and mTOR (n = 10) inhibitors using OC cell lines (n = 8) and ex vivo patient-derived cell cultures (PDCs, n = 5) to identify clinically suitable drug vulnerabilities. Targeting PCSK9 expression with siRNA or PCSK9 specific inhibitor (PF-06446846) impaired OC cell survival. In addition, overexpression of PCSK9 induced robust AKT phosphorylation along with increased expression of ERK1/2 and MEK1/2, suggesting a pro-survival role of PCSK9 in OC cells. Moreover, our drug testing revealed marked differences in cytotoxic responses to drugs targeting metabolic pathways of high-grade serous ovarian cancer (HGSOC) and low-grade serous ovarian cancer (LGSOC) PDCs. Our results show that targeting PCSK9 expression could impair OC cell survival, which warrants further investigation to address the dependency of this cancer on lipogenesis and omental metastasis. Moreover, the differences in metabolic gene expression and drug responses of OC PDCs indicate the existence of a metabolic heterogeneity within OC subtypes, which should be further explored for therapeutic improvements. en
dc.format.extent 20
dc.language.iso eng
dc.relation.ispartof Cancers
dc.rights cc_by
dc.rights.uri info:eu-repo/semantics/openAccess
dc.subject omentum
dc.subject ovarian cancers
dc.subject PCSK9
dc.subject drug testing
dc.subject mTOR
dc.subject metabolism
dc.subject rapalogs
dc.subject CELL-SURVIVAL
dc.subject DISCOVERY
dc.subject METASTASIS
dc.subject GROWTH
dc.subject DEGRADATION
dc.subject ENDOMETRIAL
dc.subject NVP-BEZ235
dc.subject 3122 Cancers
dc.title Evaluating Targeted Therapies in Ovarian Cancer Metabolism : Novel Role for PCSK9 and Second Generation mTOR Inhibitors en
dc.type Article
dc.contributor.organization Genome-Scale Biology (GSB) Research Program
dc.contributor.organization ATG - Applied Tumor Genomics
dc.contributor.organization Faculty of Medicine
dc.contributor.organization Institute for Molecular Medicine Finland
dc.contributor.organization Precision Systems Medicine
dc.description.reviewstatus Peer reviewed
dc.relation.doi https://doi.org/10.3390/cancers13153727
dc.relation.issn 2072-6694
dc.rights.accesslevel openAccess
dc.type.version publishedVersion

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