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Published in final edited form as: Nurs Res. 2021 Nov-Dec;70(6):475–480. doi: 10.1097/NNR.0000000000000547

A Possible Bioenergetic Biomarker for Chronic Cancer-Related Fatigue

Chao-Pin Hsiao 1, Barbara Daly 1, Mei-Kuang Chen 2, Marty Veigl 3, Jennifer Dorth 4, Lee Evan Ponsky 5, Charles Hoppel 5
PMCID: PMC8563391  NIHMSID: NIHMS1728264  PMID: 34380980

Abstract

Background:

Cancer-related fatigue is a highly prevalent, debilitating, and persistent symptom experienced by patients receiving cancer treatments. Up to 71% of men with prostate cancer receiving radiation therapy experience acute and persistent CRF. There is neither an effective therapy nor a diagnostic biomarker for cancer-related fatigue. This pilot study aimed to discover potential biomarkers associated with chronic cancer-related fatigue in men with prostate cancer receiving radiation therapy.

Methods:

We used a longitudinal repeated-measures research design. Twenty men with prostate cancer undergoing radiation therapy completed all study visits. Cancer-related fatigue was evaluated by a well-established and validated questionnaire, the Patient-Reported Outcomes Measurement Information System–Fatigue (PROMIS–F) Short Form. In addition, peripheral blood mononuclear cells (PBMC) were harvested to quantify ribonucleic acid (RNA) gene expression of mitochondria-related genes. Data were collected before, during, on completion, and 24 months postradiation therapy and analyzed using paired t-tests and repeated measures analysis of variance.

Results:

The mean of the PROMIS–F T-score was significantly increased over time in patients with prostate cancer, remaining elevated at 24 months post-radiation therapy compared to baseline. A significant downregulated BC1 ubiquinol-cytochrome c reductase synthesis-like (BCS1L) was observed over time during radiation therapy and at 24 months postradiation therapy. An increased PROMIS–F score was trended with downregulated BCS1L in patients 24 months after completing radiation therapy.

Discussion:

This is the first evidence to describe altered messenger RNA for BCS1L in chronic cancer-related fatigue using the PROMIS–F measure with men receiving radiation therapy for prostate cancer.

Conclusion:

Our results suggest that PBMC messenger RNA for BCS1L is a potential biomarker and therapeutic target for radiation therapy-induced chronic cancer-related fatigue in this clinical population.

Keywords: BCS1L, biomarker, cancer-related fatigue, prostate cancer, radiation therapy

Cancer-related fatigue (CRF) is the most prevalent, debilitating, and persistent symptom experienced by patients undergoing cancer treatment and substantially increases during radiation therapy (RT; (Bower, 2014; Danjoux et al., 2007; Minton et al., 2013). Prostate cancer is the second most common malignancy and the third leading cause of cancer mortality in the United States (American Cancer Society, 2021). Up to 71% of men with prostate cancer receiving RT experience significant CRF. This symptom decreases compliance with cancer treatment (Hofman et al., 2007) and negatively affects health outcomes, leading to increased depression, sleep disturbance, and impaired cognitive function, and reduced health-related quality of life (Berger & Mitchell, 2008; Byar et al., 2006; Monga et al., 1999; Pinto et al., 2013). CRF in men treated for prostate cancer has been found to increase beginning at week 3 of RT, remaining elevated at completion of RT, and lasting months to years afterward (Danjoux et al., 2007; Hsiao et al., 2013; Miaskowski et al., 2008).

Uncovering potential biomarkers associated with CRF is an essential step in developing effective and precise targets for CRF. Fourteen nuclear-encoded genes related to mitochondrial biogenesis and bioenergetics that were differentially expressed over time during RT in patients with nonmetastatic prostate cancer have been identified (Hsiao et al., 2014). Downregulated messenger ribonucleic acid (RNA), BC1 ubiquinol-cytochrome c reductase synthesis-like (BCS1L) with decreased BCS1L protein expression was significantly associated with CRF severity during and on completion of RT (Hsiao et al., 2014; Hsiao et al., 2013). Thus, a mitochondrial bioenergetic mechanism in CRF development has been proposed (Hsiao et al., 2015). This bioenergetic mechanism links dysregulation of mitochondrial genes and proteins associated with RT-induced acute CRF through a defect in complex III and oxidative phosphorylation in prostate cancer patients receiving RT (Hsiao et al., 2018). Investigation of biomarkers or mechanisms associated with persistent/chronic CRF is very limited (Feng et al., 2017). However, our preliminary findings in acute CRF demonstrated that downregulated BCS1L and reduced functional complex III activity of the mitochondrial respiratory chain were significantly associated with fatigue (Hsiao et al., 2018; Hsiao et al., 2019). Therefore, we were interested in further examining the influence of this specific potential biomarker. The purpose of this pilot study was to determine changes in RT-induced CRF and the expression level of messenger RNA for BCS1L in peripheral mononuclear cells (PBMC) among men with prostate cancer during, on completion, and 24 months post-RT, with the aim of uncovering potential PBMC biomarkers of RT-induced chronic CRF.

Methods

This was a prospective study designed to encompass repeated measurements. We hypothesized that downregulated BCS1L was associated with worsen CRF 24 months after completion of RT in patients with prostate cancer. This study was approved by the institutional review board of the Case Comprehensive Cancer Center and the University Hospitals (UH) Cleveland Medical Center.

Sample and Setting

Patients with nonmetastatic prostate cancer scheduled to receive localized RT and able to provide written informed consent were enrolled from the UH Cleveland Medical Center. Patients were excluded from the study if they had progressive disease-causing significant fatigue, documented major psychiatric illness within 5 years, had uncorrected hypothyroidism or untreated anemia, took sedatives, steroids, or nonsteroidal anti-inflammatory agents, or had a second malignancy or mitochondrial disease. After obtaining written informed consent, we collected demographic information and medical history via interviews and medical records.

Study Measures

Study variables included fatigue and BCS1L gene expression. In addition, depression was evaluated as a covariate of fatigue in this population. We collected questionnaires and peripheral blood samples from each participant before RT (baseline), on completion of RT (end point), and 24 months post-RT.

Fatigue

Patient-reported fatigue was measured using the Patient-Reported Outcomes Measurement Information System for Fatigue (PROMIS–F) Short Form. It is a valid and reliable instrument consisting of a 7-item questionnaire for fatigue (Hays et al., 2009). The PROMIS–F was developed from more than 1,000 data sets from multiple disease populations, including cancer. It can be completed in 2–3 min, and a T-score of 50 and above is considered fatigued compared to the general population (Cessna et al., 2016).

Depression

We used the Hamilton Depression Rating Scale (HAM–D) to screen the severity of depressive symptoms for each subject in the past week prior to the interview at each time point. The HAM–D is a 21-item Likert scale; 14 items are scored 0–4, and 7 are scored 0–2. Higher scores indicate worsened depressive symptoms. Good internal reliability (α = 0.81) has been reported (Hamilton, 1960). The predefined cut-off score for depression is 15 in cancer patients (Lydiatt et al., 2008). The mean total score is reported in this study.

Messenger RNA Expression of BCS1L

Total RNA (100–120ng) was extracted from PBMC following a published laboratory protocol (Hsiao et al., 2014). To quantify the changes of BCS1L, real-time polymerase chain reaction (PCR) was performed using TaqMan® chemistry from Applied Biosystems (Foster City, CA). Expression values were assessed by monitoring in real-time the PCR cycle in which a minimum level of product is produced, i.e., crosses the cycle threshold (Ct) value. The lower the Ct value, the higher the gene expression level. The expression levels were reported as delta Cts between the gene of interest and the endogenous controls. Three housekeeping genes were used as endogenous controls to adjust for the input RNA, including glyceraldehyde-3-phosphate dehydrogenase (GAPDH), β-actin (ACTB), and hypoxanthine phosphoribosyltransferase 1 (HPRT1).

Statistical Analysis

Descriptive statistics were calculated for the mean, standard deviation, standard error of the mean, and range for the participants’ demographic and clinical characteristics and gene expression. To compare the mean differences in fatigue scores and BCS1L gene expression between time points within groups, repeated measures analysis of variance and paired t-tests were used to better understand where the difference was. Following that analysis, we used the Pearson correlation to analyze the associations between fatigue and gene expression. Finally, power analysis was used to determine the sample size of 25 and 80% power with the detection of differences in fatigue scores and gene expression over time. All statistical analysis and graphics were conducted using IBM SPSS Statistics for Windows (Version 27.0) and R 4.0.0 for Windows (R Core Team, 2020).

Results

Twenty patients diagnosed with localized prostate cancer were enrolled and completed all study visits in this pilot study. Table 1 describes the demographics and clinical characteristics of the study sample. The majority of subjects had a clinical cancer tumor stage T1b or c with a Gleason score of 6–7. The baseline hemoglobin and hematocrit were in the normal range. There were no subjects who reached the cut-off score of 15 (Lazure et al., 2009) for clinical depression at baseline, and scores were low both at baseline and 24 months post-RT (M = 1.50, SD = 3.03, minimum–maximum = 0–12).

Table 1.

Demographic and Clinical Characteristics of the study participants at baseline before radiation therapy

Characteristics N (%) Mean (SD) Min-Max
Age 20 68.7 (9.4)
Race
 White 13 (65)
 African American 7 (35)
Marriage
 Married 11 (55)
 Widowed 6 (30)
 Single 2 (10)
 Divorced/Separated 1 (5)
Employment Status
 Employed full time 6 (30)
 Employed part time 1 (5)
 Retired 12 (60)
 Disabled 1 (5)
T-stage
 T1b-T1c 18 (90)
 T3a-T3b 2 (10)
Gleason Score
 6–7 13 (65)
 8–9 7 (35)
Karnofsky Performance
 80, Restricted but ambulatory 4 (35)
 90, Full active 16 (65)
Hemoglobin (mg/dL) 13.9 (1.3)
12.1–16
Hematocrit (%) 42.3 (3.8)
36.5 – 48.8
PSA 10.2 (7.1)
3.4 – 27.1
HAM-D 0.95 (1.6)
0 – 3
Total EBRT dosage (Gray)
 81 14 (70)
 100 6 (30)
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Note. SD = standard deviation; PSA = prostate specific antigen; HAM-D = Hamilton Depression Rating Scale; EBRT = external beam radiation therapy

Fatigue

Compared to the baseline (M = 47.9, SD = 6.03), the PROMIS–F fatigue score was increased significantly during and on completion of RT (M = 53.5, SD = 6.96, p < .01), remaining significantly elevated at 24 months post-RT (M = 53.8, SD = 7.02, p < .01), as shown in Figure 1. The effect sizes of the PROMIS–F were estimated using Cohen’s d (Durlak, 2009): 1.22 (95% CI [0.63, 1.79]) from baseline (Day 0) to Day 42, 1.18 (95% CI [0.58, 1.71]) from Day21 to Day 42, and 1.19 (95% CI [0.60, 1.76]) from baseline (Day 0) to 24 months post-RT.

Figure 1. Changes in fatigue score over time in patients with prostate cancer undergoing radiation therapy (N=20).

Figure 1.

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The Patient-Reported Outcomes Measurement Information System measured fatigue for Fatigue (PROMIS-F) Short Form. X-axis indicates time points: Day 0 = prior to RT; Day 21 = Day 21 of RT, midpoint; Day 42 = completion of RT, 24 months = 24 months post-RT. Y-axis represents PROMIS-F T-score. Fatigue score has significantly increased at Day 42 of RT since baseline (Day 0), remaining significantly elevated 24 months post-RT in patients with RT (p < .01).

Messenger RNA Expression Level of BCS1L

There was a significant downregulation of BCS1L in PBMC at endpoint of RT (M = 9.6, SD = 1.26, p =.03), remaining downregulated at 24 months post-RT (M = 9.6, SD = 1.24, p = .02), which was indicated by increased delta Ct number overtime, compared to the baseline delta Ct value (M = 7.8, SD = 1.31), depicted in Figure 2 (fold change > −1.5, p = .02). Moreover, downregulation of BCS1L was trended with increased CRF at 24 months post-RT (r = 0.32, p = .09), as presented in Figure 3.

Figure 2. Changes in messenger RNA expression levels of BCS1L over time in patients with prostate cancer undergoing radiation therapy (N=20).

Figure 2.

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BCS1L= BC1 (ubiquinol-cytochrome c reductase) synthesis-like.

Left chart: Y-axis represents expression values assayed by monitoring in real-time polymerase chain reaction calculated as delta cycle threshold (Ct) value/number. The BCS1L Ct value was significantly increased at Day 21 and Day 42, remaining elevated 24 months post-RT, indicating a downregulated BCS1L over time in patients with RT compared to Day 0 (p = .02).

Right chart: Y-axis represents expression values assayed by monitoring in real-time polymerase chain reaction calculated as fold change. The BCS1L fold change was significantly decreased over time (Day 21 and Day 42) and remained downregulated at 24 months post-RT (p = .03).

Figure 3. Correlation between PROMIS-F score and BCS1L delta cycle value in patients with prostate cancer 24 months post-radiation therapy (N=20).

Figure 3.

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X-axis represents the delta cycle threshold (Ct) value/number for BCS1L (BC1 ubiquinol-cytochrome c reductase synthesis-like). Y-axis represents PROMIS-F T score. The increased fatigue score was trended with increased Ct value of BCS1L, downregulation of BCS1L in patients with prostate cancer at 24 months post-RT (r = 0.32, p = .09). T4 = 24 months post-RT.

Discussion

To our knowledge, this is the first evidence to describe altered messenger RNA for BCS1L in chronic CRF using the PROMIS–F measure with men receiving RT for prostate cancer. Changes in CRF trajectory among men receiving RT for their prostate cancer are consistent with previous studies (Conaglen et al., 2013; Feng et al., 2017; Miaskowski et al., 2008). Furthermore, dysregulated mitochondrial genes including BCS1L were associated with CRF (Hsiao et al., 2019; Hsiao et al., 2014) and mitochondrial disorders (Fernandez-Vizarra et al., 2007; Oláhová et al., 2019). In addition, previous studies have shown that downregulated BCS1L was associated with reduced complex III activity and oxidation rate of mitochondria in acute CRF among patients receiving RT, compared to those without RT (Hsiao et al., 2018; Hsiao et al., 2019).

The human BCS1L gene encodes a homolog of the Saccharomyces cerevisiae bcs1 protein, which is a chaperone protein that has an essential role in the assembly of complex III and the respirasome of the mitochondrial respiratory chain (Hinson et al., 2007; Petruzzella et al., 1998). BCS1L protein facilitates the catalytic Rieske iron-sulfur (RIS) insertion into complex III during assembly of the respiratory chain, where it produces and maintains effective adenosine triphosphate (ATP) content (Hinson et al., 2007; Mandelker, 2008; Morán et al., 2010). A decrease in BCS1L protein levels has been found in patients with mitochondrial disease (e.g., complex III deficiency, GRACILE syndrome; (Fernandez-Vizarra et al., 2007; Hinson et al., 2007; Meunier et al., 2013). Decreased BCS1L protein has been shown to lead to decreased incorporation of the RIS protein into complex III in E. coli (Borisov et al., 2002). An incomplete complex III assembly was associated with decreased activity and increased electron leakage, leading to a functional deficit in the respiratory chain, resulting in ATP depletion and increased reactive oxygen species (ROS) in patients with complex III disease (Hinson et al., 2007; Meunier et al., 2013).

Studies have shown that the expression level of BCS1L was decreased by week 3 and remained in downregulation at the end of RT, associated with CRF in patients with prostate cancer (Hsiao et al., 2014; Hsiao et al., 2013). In addition, downregulation of BCS1L was associated with a decrease of complex III activity and oxidation in the mitochondrial respiratory chain in PBMC of patients with RT (Hsiao et al., 2018). RT targets rapidly dividing mitotic cells, inducing molecular-genetic damage to mitochondria (Karim et al., 2016; Zabbarova & Kanai, 2008), which might contribute to acute and chronic CRF associated with RT. Several limitations are recognized, including the lack of measurement of other variables that might affect CRF, such as cognitive function, sleep disturbance, physical activity, and diet. Additionally, this pilot study was limited by the small sample size resulting in limited power. Further investigation is warranted using a larger sample to confirm the possible molecular-genetic pathway of bioenergetics and BCS1L as a biomarker associated with CRF.

Conclusion

Our findings provide evidence that RT triggers a genetic defect in messenger RNA (mRNA) for BCS1L, which is associated with chronic CRF experienced by patients with prostate cancer 2 years after RT. We suggest that PBMC mRNA for BCS1L is a potential biomarker for RT-induced chronic CRF. The integration of genetic molecular measures into the study of CRF may provide better predictions of risk factors and identifications of prognostic biomarkers in future translational research.

Acknowledgement:

Research reported in this publication was supported by the National Institute of Nursing Research of the National Institutes of Health under Award Number K01NR015246; the Case Western Reserve University Vice President for Research (VPR) Catalyst Award, Seed Funds, and the Center for Mitochondrial Disease, Case Western Reserve University School of Medicine. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Footnotes

The authors have no conflicts of interest to report.

Ethical Conduct of Research: This research was approved by the Institutional Review Board of the Case Comprehensive Cancer Center and the University Hospitals (UH) Cleveland Medical Center.

Contributor Information

Mei-Kuang Chen, The University of Arizona Department of Psychology, Tucson, AZ.

Marty Veigl, Case Western Reserve University Comprehensive Cancer Center, Cleveland, OH.

Jennifer Dorth, Case Western Reserve University School of Medicine, Cleveland, OH.

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