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Relationships Between Expression of BCS1L, Mitochondrial Bioenergetics, and Fatigue Among Patients with Prostate Cancer

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Relationships Between Expression of BCS1L, Mitochondrial Bioenergetics, and Fatigue Among Patients with Prostate Cancer Cancer Management and Research Dovepress open access to scientific and medical research Open Access Full Text Article ORIGINAL RESEARCH Relationships between expression of BCS1L, mitochondrial bioenergetics, and fatigue among patients with prostate cancer This article was published in the following Dove Press journal: Cancer Management and Research Chao-Pin Hsiao1,2 Introduction: Cancer-related fatigue (CRF) is the most debilitating symptom with the Mei-Kuang Chen3 greatest adverse side effect on quality of life. The etiology of this symptom is still not Martina L Veigl4 understood. The purpose of this study was to examine the relationship between mitochon- Rodney Ellis5 drial gene expression, mitochondrial oxidative phosphorylation, electron transport chain Matthew Cooney6 complex activity, and fatigue in prostate cancer patients undergoing radiotherapy (XRT), Barbara Daly1 compared to patients on active surveillance (AS). Methods: The study used a matched case–control and repeated-measures research design. Charles Hoppel7 Fatigue was measured using the revised Piper Fatigue Scale from 52 patients with prostate 1The Frances Payne Bolton School of cancer. Mitochondrial oxidative phosphorylation, electron-transport chain enzymatic activity, Nursing, Case Western Reserve ’ University, Cleveland, OH, USA; 2School and BCS1L gene expression were determined using patients peripheral mononuclear cells. of Nursing, Taipei Medical University, Data were collected at three time points and analyzed using repeated measures ANOVA. 3 Taipei , Taiwan; Department of Results: The fatigue score was significantly different over time between patients undergoing XRT Psychology, University of Arizona, fi Tucson, AZ, USA; 4Gene Expression & and AS (P<0.05). Patients undergoing XRT experienced signi cantly increased fatigue at day 21 Genotyping Facility, Case Comprehensive and day 42 of XRT (P<0.01). Downregulated mitochondrial gene (BC1, ubiquinol-cytochrome Cancer Center, Case Western Reserve c reductase, synthesis-like, BCS1L, P<0.05) expression, decreased OXPHOS-complex III oxida- University, Cleveland, OH, USA; 5Department of Radiation Oncology and tion (P<0.05), and reduced activity of complex III were observed over time in patients with XRT. Urology, School of Medicine, Case Moreover, increased fatigue was significantly associated with downregulated BCS1L and Western Reserve University, Cleveland, OH, USA; 6Department of Medical decreased complex III oxidation in patients undergoing XRT. Oncology, School of Medicine, Case Conclusion: Our results suggest that BCS1L and complex III in mitochondrial mononuclear Western Reserve University, Cleveland, cells are potential biomarkers and feasible therapeutic targets for acute XRT-induced fatigue OH, USA; 7Center for Mitochondrial Disease, Department of Pharmacology in this clinical population. and Medicine, School of Medicine, Case Keywords: BCS1L, gene expression, mitochondrial bioenergetics, cancer-related fatigue, Western Reserve University, Cleveland, prostate cancer, radiation therapy OH, USA Introduction Prostate cancer is a highly prevalent carcinoma, the second most common malignancy, and the third leading cause of cancer mortality in the US. The American Cancer Society estimated 164,690 new diagnoses of this disease and 29,430 deaths in 2018.1 The survival rate of patients with locally advanced prostate cancer has greatly increased with advances Correspondence: Chao-Pin Hsiao Frances Payne Bolton School of Nursing, in primary therapies. External beam radiation therapy (XRT) using conformal techniques Case Western Reserve University, 2120 such as intensity-modulated radiation with image-guided XRT, is a standard treatment Cornell Road, Cleveland, OH 44106-4904, 2 USA option for patients with localized prostate cancer. Although XRT has increased survival Tel +1 216 368 3343 rates for men with prostate cancer, it results in numerous side effects which persist even in Fax +1 216 368 3542 3,4 Email [email protected] disease-free states including distressing fatigue during treatment. submit your manuscript | www.dovepress.com Cancer Management and Research 2019:11 6703–6717 6703 DovePress © 2019 Hsiao et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work http://doi.org/10.2147/CMAR.S203317 you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Hsiao et al Dovepress Cancer-related fatigue (CRF) is the most prevalent, carriers in the mitochondrial inner membrane. As debilitating, and persistent symptom experienced by defined,44 integrated mitochondrial function is measured patients with cancer undergoing treatment,5–8 and typically as OXPHOS and involves transport of substrates into the increases during XRT.9,10 CRF is pervasive, a whole-body mitochondria, the generation of reducing equivalents excessive tiredness or exhaustion related to the disease or (NADH and FADH2) by specific dehydrogenases, entry its treatment, unrelated to activity or exertion and not into the electron transport chain (ETC), and coupling to relieved by rest or sleep.11,12 CRF decreases compliance the production of ATP.45,46 The human BCS1L gene with cancer treatment13 and it negatively impacts other encodes a member of the ATPases associated with diverse health outcomes, leading to increased depression, impaired cellular activities (AAA) family of ATPases. The BCS1L cognitive function, increased sleep disturbance, decreased chaperone protein inserts the Rieske iron sulfur protein physical activity, and decreased health-related quality of into complex III of the respiratory chain in mitochondria, life.14–17 CRF in men treated for prostate cancer has been where the respiratory chain produces and maintains effec- found to increase beginning at week threeof XRT, increas- tive ATP content.47,48 ing significantly by week six,9 remaining elevated at the The purpose of this study was to examine the relation- completion of XRT,18 and lasting months to years ship between the expression of mitochondrial gene BCS1L, afterward.3,9,19–21 integrated mitochondrial OXPHOS, ETC enzymatic activ- With limited available options to manage CRF, strate- ity, and CRF in prostate cancer patients receiving XRT and gies are needed to identify effective interventions. To guide to compare these to patients undergoing active surveillance the development of effective therapies for the management (AS), but who had not received any treatment. of CRF, identification of pathophysiological mechanism(s) and related-biomarkers associated with CRF is an essential Material and methods step. Various attempts have been made to investigate multi- This was a prospective and case-matched study designed – factorial mechanisms of CRF,22 30 but the pathophysiologi- to encompass repeated measurements. Patients with non- cal mechanisms of CRF remain unclear. For example, metastatic prostate cancer scheduled to receive localized several mechanisms have been proposed to influence the XRT or without any treatment but on AS and able to individual CRF experience, including genetic factors, provide written informed consent were enrolled. Patients energy expenditure, metabolism, aerobic capacity, and the were excluded from the study if they had progressive – patient’s immune response to inflammation.31 33 The disease causing significant fatigue; documented major psy- inflammation hypothesis has been the primary focus for chiatric illness within five years; had uncorrected – investigations into the mechanism of CRF,27,34 36 but hypothyroidism or untreated anemia; took sedatives, ster- – some reports have indicated no association.37 39 We have oids or nonsteroidal anti-inflammatory agents; or had determined that a significant relationship exists between a second malignancy or mitochondrial disease. radiation-related fatigue and the differential expression of This study was reviewed and approved by the genes related to mitochondrial bioenergetics.40,41 More Institutional Review Board of the Case Comprehensive recently, we have shownsignificantly decreased mitochon- Cancer Center. The study conformed to the principles out- drial oxidative phosphorylation (OXPHOS) starting at com- lined in the Declaration of Helsinki. From August 2015 to plex III associated with increased fatigue in patients December 2017 we screened a total of 153 patients; 44 were receiving XRT by week three.42 ineligible and 56 refused to participate. As a result, 53 We have proposed a mechanism of mitochondrial bioe- patients were enrolled (one withdrew because of a time con- nergetics in CRF determining the relationship between flict). After obtaining written informed consent, we collected bioenergetics and XRT-induced CRF, linking downregu- demographic information and medical history via interviews lated BC1 (ubiquinol-cytochrome c reductase) synthesis- and from the medical records. Study variables included fati- like (BCS1L) and impaired OXPHOS starting at complex gue, mitochondrial bioenergetics, and BCS1L gene expres- III as causes of CRF development.43 OXPHOS is the sion. In addition, depression was evaluated
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