Expression of mitochondrial regulators PGC1α and TFAM as putative markers of subtype and chemoresistance in epithelial ovarian carcinoma

Marike Gabrielson; My Björklund; Joseph Carlson; Maria Shoshan

doi:10.1371/journal.pone.0107109

Expression of mitochondrial regulators PGC1α and TFAM as putative markers of subtype and chemoresistance in epithelial ovarian carcinoma

PLoS One. 2014 Sep 22;9(9):e107109. doi: 10.1371/journal.pone.0107109. eCollection 2014.

Authors

Marike Gabrielson¹, My Björklund¹, Joseph Carlson², Maria Shoshan¹

Affiliations

¹ Department of Oncology-Pathology, Cancer Center Karolinska CCK, Karolinska Institutet, Stockholm, Sweden.
² Department of Oncology-Pathology, Cancer Center Karolinska CCK, Karolinska Institutet, Stockholm, Sweden; Department of Pathology-Cytology, Radiumhemmet, Karolinska University Hospital, Stockholm, Sweden.

Abstract

Epithelial ovarian carcinoma (EOC), the major cause of gynaecological cancer death, is a heterogeneous disease classified into five subtypes. Each subtype has distinct clinical characteristics and is associated with different genetic risk factors and molecular events, but all are treated with surgery and platinum/taxane regimes. Tumour progression and chemoresistance is generally associated with major metabolic alterations, notably altered mitochondrial function(s). Here, we report for the first time that the expression of the mitochondrial regulators PGC1α and TFAM varies between EOC subtypes; furthermore, we have identified a profile in clear-cell carcinoma consisting of undetectability of PGC1α/TFAM, and low ERα/Ki-67. By contrast, high-grade serous carcinomas were characterised by a converse state of PGC1α/TFAM, ERα positivity and a high Ki-67 index. Interestingly, loss of PGC1α/TFAM and ERα was found also in a non-clear cell EOC cell line made highly resistant to platinum in vitro. Similar to clear-cell carcinomas, these resistant cells also showed accumulation of glycogen. Altogether, our data provide mechanistic insights into the chemoresistant nature of ovarian clear-cell carcinomas. Furthermore, these findings corroborate the need to take into account the diversity of EOC and to develop subtype specific treatment strategies.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenocarcinoma, Clear Cell / drug therapy
Adenocarcinoma, Clear Cell / genetics
Adenocarcinoma, Clear Cell / metabolism*
Adenocarcinoma, Clear Cell / pathology
Adult
Aged
Aged, 80 and over
Biomarkers, Tumor / metabolism*
Cell Line, Tumor
Cystadenocarcinoma, Serous / drug therapy
Cystadenocarcinoma, Serous / genetics
Cystadenocarcinoma, Serous / metabolism*
Cystadenocarcinoma, Serous / pathology
DNA-Binding Proteins / metabolism*
Disease Progression
Drug Resistance, Neoplasm / genetics*
Female
Glycogen / metabolism
Humans
Middle Aged
Mitochondrial Proteins / metabolism*
Ovarian Neoplasms / drug therapy
Ovarian Neoplasms / genetics
Ovarian Neoplasms / metabolism*
Ovarian Neoplasms / pathology
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
Prognosis
Transcription Factors / metabolism*

Substances

Biomarkers, Tumor
DNA-Binding Proteins
Mitochondrial Proteins
PPARGC1A protein, human
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
TFAM protein, human
Transcription Factors
Glycogen

Grants and funding

This work was supported by Swedish Cancer Society, contracts 100476 and 120814; research Council of Sweden, contract A0360901; and Radiumhemmet Research Foundation, contract 124182. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.