Proteomic Analysis Identifies NDUFS1 and ATP5O as Novel Markers for Survival Outcome in Prostate Cancer

Simple Summary Due to the heterogeneity of prostate cancer (PCa), it is still difficult to provide risk stratification. Metabolic changes in PCa tissue have been described during tumor progression at genetic and transcriptomic level, but these have not yet clearly contributed to improved diagnosis and therapy. The aim of our study was to identify novel markers for aggressive prostate cancer in a proteomics-derived dataset by immunohistochemical analysis and correlation with transcriptomic data. Here, we provide potential new markers—NDUFS1 and ATP5O—for risk stratification in PCa. Additionally, we reveal for the first time a concordant increase of NDUFS1/ATP5O of mRNA expression in transcriptomic datasets and at protein level. Abstract We aimed to identify novel markers for aggressive prostate cancer in a STAT3-low proteomics-derived dataset of mitochondrial proteins by immunohistochemical analysis and correlation with transcriptomic data and biochemical recurrence in a STAT3 independent PCa cohort. Formalin-fixed paraffin-embedded tissue (FFPE) sample selection for proteomic analysis and tissue-microarray (TMA) generation was conducted from a cohort of PCa patients. Retrospective data analysis was performed with the same cohort. 153 proteins differentially expressed between STAT3-low and STAT3-high samples were identified. Out of these, 46 proteins were associated with mitochondrial processes including oxidative phosphorylation (OXPHOS), and 45 proteins were upregulated, including NDUFS1/ATP5O. In a STAT3 independent PCa cohort, high expression of NDUFS1/ATP5O was confirmed by immunocytochemistry (IHC) and was significantly associated with earlier biochemical recurrence (BCR). mRNA expression levels for these two genes were significantly higher in intra-epithelial neoplasia and in PCa compared to benign prostate glands. NDUFS1/ATP5O levels are increased both at the mRNA and protein level in aggressive PCa. Our results provide evidence that NDUFS1/ATP5O could be used to identify high-risk PCa patients.

[1]  L. Kenner,et al.  The Implications of PDK1–4 on Tumor Energy Metabolism, Aggressiveness and Therapy Resistance , 2020, Frontiers in Oncology.

[2]  Angela N. Brooks,et al.  Visualizing and interpreting cancer genomics data via the Xena platform , 2020, Nature Biotechnology.

[3]  M. Mann,et al.  STAT3‐dependent analysis reveals PDK4 as independent predictor of recurrence in prostate cancer , 2020, Molecular systems biology.

[4]  M. Schuldiner,et al.  Disease-causing mutations in subunits of OXPHOS complex I affect certain physical interactions , 2019, Scientific Reports.

[5]  Prashanth Rawla,et al.  Epidemiology of Prostate Cancer , 2019, World journal of oncology.

[6]  N. Thapa,et al.  ATP Synthase: Structure, Function and Inhibition , 2019, Biomolecular concepts.

[7]  S. Srihari,et al.  Metabolic deregulation in prostate cancer. , 2018, Molecular omics.

[8]  V. Vasioukhin,et al.  Recent advances in prostate cancer research: large-scale genomic analyses reveal novel driver mutations and DNA repair defects , 2018, F1000Research.

[9]  F. Saad,et al.  Landmarks in prostate cancer , 2018, Nature Reviews Urology.

[10]  M. Nykter,et al.  Integrative proteomics in prostate cancer uncovers robustness against genomic and transcriptomic aberrations during disease progression , 2018, Nature Communications.

[11]  L. Galluzzi,et al.  Mitochondrial metabolism and cancer , 2017, Cell Research.

[12]  Alba Timón-Gómez,et al.  Mitochondrial cytochrome c oxidase biogenesis: Recent developments. , 2017, Seminars in cell & developmental biology.

[13]  Michael P. Lisanti,et al.  Mitochondrial biomarkers predict tumor progression and poor overall survival in gastric cancers: Companion diagnostics for personalized medicine , 2017, Oncotarget.

[14]  G. Kristiansen,et al.  Systematic Expression Analysis of Mitochondrial Complex I Identifies NDUFS1 as a Biomarker in Clear‐Cell Renal‐Cell Carcinoma , 2017, Clinical genitourinary cancer.

[15]  G. Kristiansen,et al.  Systematic Analysis of the Expression of the Mitochondrial ATP Synthase (Complex V) Subunits in Clear Cell Renal Cell Carcinoma , 2017, Translational oncology.

[16]  Eric Eidelman,et al.  The Metabolic Phenotype of Prostate Cancer , 2017, Front. Oncol..

[17]  Mary Goldman,et al.  Toil enables reproducible, open source, big biomedical data analyses , 2017, Nature Biotechnology.

[18]  J. Neuzil,et al.  Mitochondrial Complex II: At the Crossroads. , 2017, Trends in biochemical sciences.

[19]  E. Giannoni,et al.  Metabolic shift toward oxidative phosphorylation in docetaxel resistant prostate cancer cells , 2016, Oncotarget.

[20]  M. Hsiao,et al.  The opposite prognostic effect of NDUFS1 and NDUFS8 in lung cancer reflects the oncojanus role of mitochondrial complex I , 2016, Scientific Reports.

[21]  Marco Y. Hein,et al.  The Perseus computational platform for comprehensive analysis of (prote)omics data , 2016, Nature Methods.

[22]  Kate L. Hertweck,et al.  Complex‐I Alteration and Enhanced Mitochondrial Fusion Are Associated With Prostate Cancer Progression , 2016, Journal of cellular physiology.

[23]  Pär Stattin,et al.  The Proteome of Primary Prostate Cancer. , 2016, European urology.

[24]  R. Aebersold,et al.  On the Dependency of Cellular Protein Levels on mRNA Abundance , 2016, Cell.

[25]  L. Egevad,et al.  A Contemporary Prostate Cancer Grading System: A Validated Alternative to the Gleason Score. , 2016, European urology.

[26]  B. Delahunt,et al.  The 2014 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason Grading of Prostatic Carcinoma: Definition of Grading Patterns and Proposal for a New Grading System , 2015, The American journal of surgical pathology.

[27]  D. Levy,et al.  STAT3 regulated ARF expression suppresses prostate cancer metastasis , 2015, Nature Communications.

[28]  E. Giannoni,et al.  Targeting stromal-induced pyruvate kinase M2 nuclear translocation impairs OXPHOS and prostate cancer metastatic spread , 2015, Oncotarget.

[29]  Lawrence D. True,et al.  Integrative Clinical Genomics of Advanced Prostate Cancer , 2015, Cell.

[30]  A. Chinnaiyan,et al.  Heterogeneity in the inter-tumor transcriptome of high risk prostate cancer , 2014, Genome Biology.

[31]  P. Stattin,et al.  Population based study of use and determinants of active surveillance and watchful waiting for low and intermediate risk prostate cancer. , 2013, The Journal of urology.

[32]  O. Sartor,et al.  Current clinical challenges in prostate cancer , 2013, Translational andrology and urology.

[33]  Ellen T. Gelfand,et al.  The Genotype-Tissue Expression (GTEx) project , 2013, Nature Genetics.

[34]  D. Wallace.  Mitochondria and cancer , 2012, Nature Reviews Cancer.

[35]  Chi V Dang,et al.  Links between metabolism and cancer. , 2012, Genes & development.

[36]  E. Marcotte,et al.  Insights into the regulation of protein abundance from proteomic and transcriptomic analyses , 2012, Nature Reviews Genetics.

[37]  S. Koochekpour,et al.  Androgen receptor signaling and mutations in prostate cancer. , 2010, Asian journal of andrology.

[38]  C. Sander,et al.  Integrative genomic profiling of human prostate cancer. , 2010, Cancer cell.

[39]  J. Smeitink,et al.  Mitochondrial complex I: Structure, function and pathology , 2006, Journal of Inherited Metabolic Disease.

[40]  David A. Bader,et al.  Prostate Cancer Energetics and Biosynthesis. , 2019, Advances in experimental medicine and biology.

[41]  J. S. Sousa,et al.  Mitochondrial Respiratory Chain Complexes. , 2018, Sub-cellular biochemistry.

[42]  T. Barrette,et al.  ONCOMINE: a cancer microarray database and integrated data-mining platform. , 2004, Neoplasia.