Differential Expression of Genes Related to Mitochondrial Biogenesis and Bioenergetics in Fatigued Prostate Cancer Men Receiving External Beam Radiation Therapy

Abstract

Objectives This prospective study explored relationships between expression changes of genes related to mitochondrial biogenesis/bioenergetics and fatigue in men with prostate cancer receiving external beam radiation therapy (EBRT). Methods Fatigue and gene expression were measured before (day 0), at midpoint (days 19-21), and at completion (days 38-42) of EBRT using the seven-item Patient Reported Outcomes Measurement Information System-Fatigue short form (PROMIS-F), and from whole blood cell RNA, respectively. The human mitochondria RT2 Profiler™ PCR Array system was used to identify differential expression of mitochondrial biogenesis/bioenergetics-related genes. Mixed linear modeling estimated the changes in fatigue and gene expression over time and determined significant associations between gene expression and fatigue. Results Subjects were 50 men with prostate cancer (scheduled for EBRT = 25, active surveillance as matched controls = 25). The mean PROMIS fatigue T-score (mean = 50 ± 10 in a general population) for study subjects was 44.87 ± 5.89 and for controls was 43.5 ± 2.8 at baseline. Differential expression of two genes inside the mitochondria involved in critical mitochondrial complexes: BCS1L (β =1.30), SLC25A37 (β = −2.44) and two genes on the outer mitochondrial membrane vital for mitochondrial integrity: BCL2L1 (β = −1.68), and FIS1 (β = −2.35) were significantly associated with changes in fatigue scores of study subjects during EBRT. Conclusion Genes related to oxidative phosphorylation, energy production and mitochondrial membrane integrity are associated with worsening fatigue during EBRT. Further investigation of the pathways involved with this association may explain mechanisms behind the development of fatigue in this population.

Association between Mitochondrial Bioenergetics and Radiation- Related Fatigue: A Possible Mechanism and Novel Target

“…In our preliminary work [55], the BCS1L average ± standard deviation expression values at baseline, midpoint, and endpoint were 6.60 ± 1.22, 7.76 ± 1.64, and 7.64 ± 1.29, respectively, in prostate cancer patients with EBRT. Given this, for our proposed study, a sample size of 22 will achieve at least 80% power to detect a mean of paired differences of 0.58 (half of 1.15) with an estimated standard deviation of differences of 0.93 using a one-sided paired t-test and level of significance 0.05.…”

“…Figure 1 depicts that one down-regulated gene, BC1 (ubiquinol-cytochrome c reductase) synthesis-like (BCS1L) and 3 up-regulated genes (BCL2-like1, (BCL2L1), solute carrier family 25, member 37(SLC25A37), and fission 1 homolog (S. cerevisiae) (FIS1) were differentiated expressed during XRT in fatigue men with prostate cancer. These genes were significantly associated with fatigue scores (β= 1.3-2.4, p= 0.001) at the completion of radiotherapy compared to the baseline [38].…”

“…Differential expression of two genes inside the mitochondria involved in critical mitochondrial complexes: BCS1L (β=1.30), SLC25A37 (β=-2.44) and two genes on the outer mitochondrial membrane vital for mitochondrial integrity: BCL2L1 (β=-1.68), and FIS1 (β=-2.35) were significantly associated with changes in fatigue scores of study subjects during EBRT [38]. Additionally, altered gene expressions were accompanied by changes of protein concentrations in peripheral cell lysates [9,38].…”

“…Additionally, altered gene expressions were accompanied by changes of protein concentrations in peripheral cell lysates [9,38].…”

“…Our previous study has shown that changes in mitochondrial-related gene expression (e.g. down-regulation of BCS1L and up-regulation of SLC25A37) in lymphocytes were associated with fatigue symptoms experienced by men with nonmetastatic prostate cancer during XRT [9,38]. Decreased BCS1L protein has been shown to lead to decreased incorporation of the Rieske iron-sulfur protein into complex III and decreased activity of complex III [39].…”