Metabolic markers GAPDH, PKM2, ATP5B and BEC-index in advanced serous ovarian cancer

Elisabet Hjerpe,Maria Shoshan,Hemming Johansson,Marianne Frostvik Stolt,Joseph Carlson,Suzanne Egyhazi Brage,Elisabeth Åvall-Lundqvist,Kjell Schedvins

doi:10.1186/1472-6890-13-30

Abstract

BackgroundA deregulated energy metabolism is a hallmark of malignant disease that offers possible future targets for treatment. We investigated the prognostic value of the glycolytic enzymes glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and pyruvate kinase type M2 (PKM2), mitochondrial β-F1-ATPase (ATP5B) and the bioenergetic cellular (BEC) index in advanced ovarian cancer.MethodsFresh tumor samples were prospectively collected from 123 patients undergoing primary surgery for suspected advanced ovarian cancer. Of these, 57 met the eligibility criteria; stage IIC-IV, serous or endometrioid subtype, specimens containing ≥ 50% tumor cells and patients receiving platinum-based chemotherapy. An adequate amount of mRNA could be extracted in all but one case, with a resultant study population of 56 patients. Eighty-six percent of cases had serous tumors, and 93% were grade 2–3. GAPDH, PKM2 and ATP5B mRNA- and protein expression was assessed by real-time PCR and immunohistochemistry. We estimated the association with platinum-free interval (PFI) and overall survival (OS) by Cox proportional hazards models. Median follow-up was 60 months.ResultsHigh GAPDH mRNA levels (HR 2.1, 95% CI 1.0-4.5) and low BEC-index (HR 0.47, 95% CI 0.23-0.95) were both independently associated with shorter PFI. Median PFI for patients with high GAPDH mRNA was 5.0 months compared to 10.1 months for low expression cases (p = 0.031). Similarly, median PFI for patients with low BEC-index based on mRNA was 5.3 months compared to 9.8 months for high BEC-index cases (p = 0.028).ConclusionsHigh GAPDH or low BEC-index mRNA expression indicate early disease progression in advanced serous ovarian cancer.

Highlights

A deregulated energy metabolism is a hallmark of malignant disease that offers possible future targets for treatment
In the present study we investigated the mRNA and protein expression of glyceraldehyde 3-phosphate dehydrogenase (GAPDH), pyruvate kinase type M2 (PKM2) and ATP5B in 56 advanced serous or endometrioid ovarian cancers, to test their ability to predict length of platinum-free interval and survival
High GAPDH mRNA expression was associated with shorter platinum-free interval (PFI) (HR 2.1, 95% CI 1.1-4.0, Figure 2 Platinum-free interval (PFI) and overall survival (OS) according to GAPDH and bioenergetic cellular (BEC)-index mRNA expression

Summary

Introduction

A deregulated energy metabolism is a hallmark of malignant disease that offers possible future targets for treatment. We investigated the prognostic value of the glycolytic enzymes glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and pyruvate kinase type M2 (PKM2), mitochondrial β-F1-ATPase (ATP5B) and the bioenergetic cellular (BEC) index in advanced ovarian cancer. A reprogrammed energy metabolism has recently been designated a “new” hallmark of cancer [2] These metabolic changes, including increased aerobic glycolysis, decreased oxidative phosphorylation and increased glutaminolysis and fatty acid-metabolism, are known features of cancer, which often correlate with an overall poor prognosis [3,4]. First introduced by Cuezva and co-workers in 2002 [3], a bioenergetic cellular index (BEC-index), based on the protein levels of mitochondrial β-F1-ATPase (ATP5B, the catalytic subunit of the rate-limiting enzyme of oxidative phosphorylation), heat-shock protein 60 (HSP60, a mitochondrial chaperone), and glycolytic GAPDH, has been shown to be of prognostic value in several cancer types such as colon, lung and breast carcinomas [3,9,10]. The expression of above metabolic markers has not yet been studied in EOC

Methods

Results

Discussion

Conclusion