Oncotarget

Research Papers:

UCP2 and PRMT1 are key prognostic markers for lung carcinoma patients

Corina T. Madreiter-Sokolowski, Balázs Győrffy, Christiane Klec, Armin A. Sokolowski, Rene Rost, Markus Waldeck-Weiermair, Roland Malli, Wolfgang F. Graier _

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Oncotarget. 2017; 8:80278-80285. https://doi.org/10.18632/oncotarget.20571

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Abstract

Corina T. Madreiter-Sokolowski1, Balázs Győrffy3,4, Christiane Klec1, Armin A. Sokolowski2, Rene Rost1, Markus Waldeck-Weiermair1, Roland Malli1 and Wolfgang F. Graier1

1 Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria

2 Dentistry and Maxillofacial Surgery, Medical University of Graz, Graz, Austria

3 MTA TTK Lendület Cancer Biomarker Research Group, Institute of Enzymology, Budapest, Hungary

4 2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary

Correspondence to:

Wolfgang F. Graier, email:

Keywords: lung cancer cell proliferation, mitochondria, Ca2+ controls respiration, protein arginine methyltransferase 1, uncoupling protein 2

Received: July 14, 2017 Accepted: August 15, 2017 Published: August 28, 2017

Abstract

Cancer cells have developed unique strategies to meet their high energy demand. Therefore, they have established a setting of Ca2+-triggered high mitochondrial activity. But mitochondrial Ca2+ uptake has to be strictly controlled to avoid mitochondrial Ca2+ overload that would cause apoptotic cell death. Methylation by protein arginine methyl transferase 1 (PRMT1) desensitizes the mitochondrial Ca2+ uptake machinery and reduces mitochondrial Ca2+ accumulation in cancer cells. In case of PRMT1-driven methylation, proper mitochondrial Ca2+ uptake is reestablished by increased activity of uncoupling protein 2 (UCP2), pointing to an importance of these proteins for cancer cell survival and activity. Accordingly, in this study we investigated the impact of UCP2 and PRMT1 on the fate of human lung cancer cells (A549, Calu-3 and H1299) as well as on patients suffering from lung carcinoma. We show that combined overexpression of UCP2 and PRMT1 significantly enhances viability, proliferation as well as mitochondrial respiration. In line with these findings, the overall survival probability of lung carcinoma patients with high mRNA expression levels of UCP2 and PRMT1 is strongly reduced. Furthermore, analysis via The Cancer Genome Atlas (TCGA) reveals upregulation of both proteins, UCP2 and PRMT1, as common feature of various cancer types. These findings suggest that proper mitochondrial Ca2+ uptake is essential for devastating tumor growth, and highlight the importance of a tightly controlled mitochondrial Ca2+ uptake to ensure proper ATP biosynthesis while avoiding dangerous mitochondrial Ca2+ overload. By that, the study unveils proteins of the mitochondrial Ca2+ uptake as potential targets for cancer treatment.


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