Evaluating targeted therapies in ovarian cancer metabolism: Novel role for pcsk9 and second generation mtor inhibitors

Dafne Jacome Sanz; Juuli Raivola; Hanna Karvonen; Mariliina Arjama; Harlan Barker; Astrid Murumägi; Daniela Ungureanu

doi:10.3390/cancers13153727

Evaluating targeted therapies in ovarian cancer metabolism: Novel role for pcsk9 and second generation mtor inhibitors

Dafne Jacome Sanz, Juuli Raivola, Hanna Karvonen, Mariliina Arjama, Harlan Barker, Astrid Murumägi, Daniela Ungureanu

Research output: Contribution to journal › Article › Scientific › peer-review

18 Citations (Scopus)

40 Downloads (Pure)

Abstract

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 addi-tion, 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.

Original language	English
Article number	3727
Journal	Cancers
Volume	13
Issue number	15
DOIs	https://doi.org/10.3390/cancers13153727
Publication status	Published - Jul 2021
Publication type	A1 Journal article-refereed

Funding

This research was funded by the Academy of Finland (grant 333583 and grant 312042 to Center of Excellence in Tumor Genetics Research), Cancer Society of Finland and Sigrid Jus?lius Foundation to D.U., A.M. and M.A.; Emil Aaltonen Foundation and Finnish Cultural Foundation ? Pirkanmaa Regional Fund to H.K.; Tampere University Doctoral Programme in Medicine and Health Technology to D.J.S. and H.B.; K. Albin Johansson Foundation and P?ivikki and Sakari Sohlberg Foundation to D.J.S.; Fimlab to H.B. Funding: This research was funded by the Academy of Finland (grant 333583 and grant 312042 to Center of Excellence in Tumor Genetics Research), Cancer Society of Finland and Sigrid Jusélius Foundation to D.U., A.M. and M.A.; Emil Aaltonen Foundation and Finnish Cultural Foundation – Pirkanmaa Regional Fund to H.K.; Tampere University Doctoral Programme in Medicine and Health Technology to D.J.S. and H.B.; K. Albin Johansson Foundation and Päivikki and Sakari Sohlberg Foundation to D.J.S.; Fimlab to H.B.

Keywords

Drug testing
Metabolism
MTOR
Omentum
Ovarian cancers
PCSK9
Rapalogs

Publication forum classification

Publication forum level 1

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.3390/cancers13153727Licence: CC BY

cancers-13-03727Final published version, 1.27 MBLicence: CC BY

http://urn.fi/URN:NBN:fi:tuni-202108116510Licence: CC BY

Cite this

@article{5e523d1bc37645a198b663c939336b2d,

title = "Evaluating targeted therapies in ovarian cancer metabolism: Novel role for pcsk9 and second generation mtor inhibitors",

abstract = "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 addi-tion, 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.",

keywords = "Drug testing, Metabolism, MTOR, Omentum, Ovarian cancers, PCSK9, Rapalogs",

author = "{Jacome Sanz}, Dafne and Juuli Raivola and Hanna Karvonen and Mariliina Arjama and Harlan Barker and Astrid Murum{\"a}gi and Daniela Ungureanu",

note = "Funding Information: This research was funded by the Academy of Finland (grant 333583 and grant 312042 to Center of Excellence in Tumor Genetics Research), Cancer Society of Finland and Sigrid Jus?lius Foundation to D.U., A.M. and M.A.; Emil Aaltonen Foundation and Finnish Cultural Foundation ? Pirkanmaa Regional Fund to H.K.; Tampere University Doctoral Programme in Medicine and Health Technology to D.J.S. and H.B.; K. Albin Johansson Foundation and P?ivikki and Sakari Sohlberg Foundation to D.J.S.; Fimlab to H.B. Funding Information: Funding: This research was funded by the Academy of Finland (grant 333583 and grant 312042 to Center of Excellence in Tumor Genetics Research), Cancer Society of Finland and Sigrid Jus{\'e}lius Foundation to D.U., A.M. and M.A.; Emil Aaltonen Foundation and Finnish Cultural Foundation – Pirkanmaa Regional Fund to H.K.; Tampere University Doctoral Programme in Medicine and Health Technology to D.J.S. and H.B.; K. Albin Johansson Foundation and P{\"a}ivikki and Sakari Sohlberg Foundation to D.J.S.; Fimlab to H.B. Publisher Copyright: {\textcopyright} 2021 by the authors. Licensee MDPI, Basel, Switzerland.",

year = "2021",

month = jul,

doi = "10.3390/cancers13153727",

language = "English",

volume = "13",

number = "15",

}

TY - JOUR

T1 - Evaluating targeted therapies in ovarian cancer metabolism

T2 - Novel role for pcsk9 and second generation mtor inhibitors

AU - Jacome Sanz, Dafne

AU - Raivola, Juuli

AU - Karvonen, Hanna

AU - Arjama, Mariliina

AU - Barker, Harlan

AU - Murumägi, Astrid

AU - Ungureanu, Daniela

N1 - Funding Information: This research was funded by the Academy of Finland (grant 333583 and grant 312042 to Center of Excellence in Tumor Genetics Research), Cancer Society of Finland and Sigrid Jus?lius Foundation to D.U., A.M. and M.A.; Emil Aaltonen Foundation and Finnish Cultural Foundation ? Pirkanmaa Regional Fund to H.K.; Tampere University Doctoral Programme in Medicine and Health Technology to D.J.S. and H.B.; K. Albin Johansson Foundation and P?ivikki and Sakari Sohlberg Foundation to D.J.S.; Fimlab to H.B. Funding Information: Funding: This research was funded by the Academy of Finland (grant 333583 and grant 312042 to Center of Excellence in Tumor Genetics Research), Cancer Society of Finland and Sigrid Jusélius Foundation to D.U., A.M. and M.A.; Emil Aaltonen Foundation and Finnish Cultural Foundation – Pirkanmaa Regional Fund to H.K.; Tampere University Doctoral Programme in Medicine and Health Technology to D.J.S. and H.B.; K. Albin Johansson Foundation and Päivikki and Sakari Sohlberg Foundation to D.J.S.; Fimlab to H.B. Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

PY - 2021/7

Y1 - 2021/7

N2 - 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 addi-tion, 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.

AB - 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 addi-tion, 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.

KW - Drug testing

KW - Metabolism

KW - MTOR

KW - Omentum

KW - Ovarian cancers

KW - PCSK9

KW - Rapalogs

U2 - 10.3390/cancers13153727

DO - 10.3390/cancers13153727

M3 - Article

AN - SCOPUS:85111046060

SN - 2072-6694

VL - 13

JO - Cancers

JF - Cancers

IS - 15

M1 - 3727

ER -

Evaluating targeted therapies in ovarian cancer metabolism: Novel role for pcsk9 and second generation mtor inhibitors

Abstract

Funding

Keywords

Publication forum classification

ASJC Scopus subject areas

UN SDGs

Access to Document

Fingerprint

Cite this