Rebecca S Arnold

Emory University, Atlanta, Georgia, United States

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Publications (52)267.49 Total impact

  • Qian Sun · Rebecca S. Arnold · Carrie Q Sun · John A Petros ·
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    ABSTRACT: Background Statins, 3-hydroxy-3 methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, are currently the most widely used cholesterol-lowering drugs. Previous epidemiological studies have suggested that there may be be an association between statin use and decreased risk of prostate cancer progression. Both inherited and somatic mutations of the mitochondrial genome are linked to prostate cancer. The purpose of this study was to determine if mitochondrial DNA (mtDNA) background and hence mitochondrial biochemistry can modulate the efficiency of statin as an anti-prostate cancer agent.Methods Cytoplasmic hybrid (cybrid) cell lines were constructed that contained a prostate cancer nucleus and either wild type or mutant mtDNA derived from a prostate cancer patient with the cytochrome oxidase subunit 1 gene mutation T6124C (Met74Thr). Multiple clones for each genotype were tested. After treating both wild type and mutant cells with increasing concentrations of simvastatin for 72 hr, cell proliferation and apoptosis were analyzed.ResultsSimvastatin inhibited both wild type and mutant cell proliferation. However, cells with the T6124C mtDNA mutation were more resistant to drug treatment than the wild type cells. In addition, analysis of caspase 3 assays and multiple proteins involved in cellular apoptosis demonstrated that mutant cells were more resistant to simvastatin treatment-induced apoptosis than wild type control cells.Conclusions Simvastatin treatment induced apoptosis in human cybrid prostate cancer cells. The response to drug treatments was different depending on mitochondrial genotype. Therefore, the degree to which statins may affect prostate cancer progression may vary based on an individual's mtDNA background. Prostate. © 2015 Wiley Periodicals, Inc.
    The Prostate 09/2015; 75(16). DOI:10.1002/pros.23089 · 3.57 Impact Factor
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    ABSTRACT: (-)-Solenopsin A is a piperidine alkaloid that is a component of the venom of the fire ant Solenopsis invicta. Previously, we have demonstrated that solenopsin exhibit anti-angiogenic activity and downregulate phosphoinositol-3 kinase (PI3K) in the p53 deficient renal cell carcinoma cell line 786-O. Solenopsin has structural similarities to ceramide, a major endogenous regulator of cell signaling and cancer therapy induced apoptosis. Different analogs of solenopsin were synthesized in order to explore structure-activity relationships. The anti-proliferative effect of solenopsin and analogs was tested on six different cell lines, including three tumor cell lines, two normal cutaneous cell lines, and one immortalized hyperproliferative cell line. FRET-based reporters were used to study the affect of solenopsin and analogs on Akt activity and PDK1 activation and sucrose density gradient fractionation was performed to examine recruitment of PTEN to membrane rafts. Western-blotting was used to evaluate the affect of solenopsin and analogs on the Akt and the MAPK 44/42 pathways in three different tumor cell lines. Measurement of cellular oxygen consumption rate together with autophagy staining was performed to study mitochondrial function. Finally, the affect of solenopsin and analogs on ROS production was investigated. In this paper we demonstrate that solenopsin analogs with potent anti-proliferative effects can be synthesized from inexpensive dimethylpyridines. To determine whether solenopsin and analogs act as ceramide analogs, we examined the effect of solenopsin and analogs on two stereotypic sites of ceramide activity, namely at lipid rafts and mitochondria. We found that native solenopsin, (-)-solenopsin A, inhibits functional Akt activity and PDK1 activation in lipid rafts in a similar fashion as ceramide. Both cis and trans analogs of solenopsin reduce mitochondrial oxygen consumption, increase reactive oxygen, and kill tumor cells with elevated levels of Akt phosphorylation. However, only solenopsin induces mitophagy, like ceramide. The requirements for ceramide induced mitophagy and inhibition of Akt activity and PDK1 activation in lipid rafts are under strict stereochemical control. The naturally occurring (-)-solenopsin A mimic some of the functions of ceramide and may be therapeutically useful in the treatment of hyperproliferative and malignant disorders of the skin, even in the presence of elevated levels of Akt.
    Vascular Cell 05/2015; 7(1). DOI:10.1186/s13221-015-0030-2
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    ABSTRACT: Background: Cancer progression and metastasis occur such that cells with acquired mutations enhancing growth and survival (or inhibiting cell death) increase in number, a concept that has been recognized as analogous to Darwinian evolution of species since Peter C. Nowell's description in 1976. Selective forces include those intrinsic to the host (including metastatic site) as well as those resulting from anti-cancer therapies. By examining the mutational status of multiple tumor sites within an individual patient some insight may be gained into those genetic variants that enhance site-specific metastasis. By comparing these data across multiple individuals, recurrent patterns may identify alterations that are fundamental to successful site-specific metastasis. Methods: We sequenced the mitochondrial genome in 10 prostate cancer patients with bone metastases enrolled in a rapid autopsy program. Patients had late stage disease and received androgen ablation and frequently other systemic therapies. For each of 9 patients, 4 separate tissues were sequenced: the primary prostate cancer, a soft tissue metastasis, a bone metastasis and an uninvolved normal tissue that served as the non-cancerous control. An additional (10th) patient had no primary prostate available for sequencing but had both metastatic sites (and control DNA) sequenced. We then examined the number and location of somatically acquired mitochondrial DNA (mtDNA) mutations in the primary tumor and two metastatic sites in each individual patient. Finally, we compared patients with each other to determine any common patterns of somatic mutation. Results: Somatic mutations were significantly more numerous in the bone compared to either the primary tumor or soft tissue metastases. A missense mutation at nucleotide position (n.p.) 10398 (A10398G; Thr114Ala) in the respiratory complex I gene ND3 was the most common (7 of 10 patients) and was detected only in the bone. Other notable somatic mutations that occurred in more than one patient include a tRNA Arg mutation at n.p. 10436 and a tRNA Thr mutation at n.p. 15928. The tRNA Arg mutation was restricted to bone metastases and occurred in three of 10 patients (30%). Somatic mutation at 15928 was not restricted to the bone and also occurred in three patients. Conclusions: Mitochondrial genomic variation was greater in metastatic sites than in the primary tumor and bone metastases had statistically significantly greater numbers of somatic mutations than either the primary or the soft tissue metastases. The genome was not mutated randomly. At least one mutational "hot-spot" was identified at the individual base level (nucleotide position 10398 in bone metastases) indicating a pervasive selective pressure for bone metastatic cells that had acquired the 10398 mtDNA mutation. Two additional recurrent mutations (tRNA Arg and tRNA Thr) support the concept of bone site-specific "survival of the fittest" as revealed by variation in the mitochondrial genome and selective pressure exerted by the metastatic site.
    Bone 05/2015; 78. DOI:10.1016/j.bone.2015.04.046 · 3.97 Impact Factor
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    The Journal of Urology 04/2015; 193(4):e557. DOI:10.1016/j.juro.2015.02.1535 · 4.47 Impact Factor
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    ABSTRACT: Introduction and objectives: There are over 65,000 new cases of renal cell carcinoma (RCC) each year, yet there is no effective clinical screening test for RCC. A single report claimed no overlap between urine levels of aquaporin-1 (AQP1) in patients with and without RCC (Mayo Clin Proc. 85:413, 2010). Here, we used archived and fresh RCC patient urine to validate this report. Methods: Archived RCC, fresh prenephrectomy RCC, and non-RCC negative control urines were processed for Western blot analysis. Urinary creatinine concentrations were quantified by the Jaffe reaction (Nephron 16:31, 1976). Precipitated protein was dissolved in 1x SDS for a final concentration of 2 μg/µL creatinine. Results: Negative control and archived RCC patient urine failed to show any AQP1 protein by Western blot analysis. Fresh RCC patient urine is robustly positive for AQP1. There was no signal overlap between fresh RCC and negative control, making differentiation straightforward. Conclusions: Our data confirms that fresh urine of patients with RCC contains easily detectable AQP1 protein. However, archival specimens showed an absence of detectable AQP1 indistinguishable from negative control. These findings suggest that a clinically applicable diagnostic test for AQP1 in fresh urine may be useful for detecting RCC.
    Disease markers 04/2014; 2014:135649. DOI:10.1155/2014/135649 · 1.56 Impact Factor
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    ABSTRACT: Aberrant promoter methylation turns off gene expression and is involved in human malignancy. Studies have shown first exon methylation to have tighter association with gene silencing when compared to promoter methylation or gene mutations. However, clinical importance of exonic methylation in renal cell carcinoma (RCC) is unknown. We analyzed RCC tumors for exonic methylation of the von Hippel-Lindau (VHL) gene using Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (MALDI-TOF MS). Forty-eight institutionally-banked RCC patient tissue samples underwent VHL exon sequencing as well as methylation analysis of both promoter and exon one by either mass spectrometry or conventional bisulfite analysis. 0% and 100% methylated human lymphocytic DNA, non-template dH2O, and two human RCC cell lines (UOK121, UOK171) were used as assay controls. Samples were called hypermethylated if a CpG site exhibited greater than 50% methylation. Forty-three patient samples were read by our exon one assay; nine had methylated VHL exon one sites, with three showing hypermethylation. Exon one methylation assay was robust and reproducible. Samples with exon one hypermethylation did not exhibit exonic mutations. All samples assayed at VHL exon two were hypermethylated. Using MALDI-TOF MS to assay RCC tumors for VHL methylation is robust and reproducible and capable of quantifying methylation status of individual DNA bases. Exon one methylation may be an alternate mechanism of VHL gene silencing in RCC in addition to mutation and promoter methylation. The application of this assay in patient populations may allow enhanced diagnosis or tumor-typing in the future.
    The Journal of urology 04/2014; 192(5). DOI:10.1016/j.juro.2014.03.108 · 4.47 Impact Factor
  • Qian Sun · Carrie Q. Sun · Rebecca S. Arnold · John A. Petros ·

    The Journal of Urology 04/2014; 191(4):e580. DOI:10.1016/j.juro.2014.02.1611 · 4.47 Impact Factor
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    ABSTRACT: Snail transcription factor can induce epithelial-mesenchymal transition (EMT), associated with decreased cell adhesion-associated molecules like E-cadherin, increased mesenchymal markers like vimentin, leading to increased motility, invasion and metastasis. Muscadine grape skin extract (MSKE) has been shown to inhibit prostate cancer cell growth and induce apoptosis without affecting normal prostate epithelial cells. We investigated novel molecular mechanisms by which Snail promotes EMT in prostate cancer cells via Reactive Oxygen Species (ROS) and whether it can be antagonized by MSKE. ARCaP and LNCaP cells overexpressing Snail were utilized to examine levels of reactive oxygen species (ROS), specifically, superoxide, in vitro using Dihydroethidium (DHE) or HydroCy3 dyes. Mitosox staining was performed to determine whether the source of ROS was mitochondrial in origin. We also investigated the effect of Muscadine grape skin extract (MSKE) on EMT marker expression by western blot analysis. Migration and cell viability using MTS proliferation assay was performed following MSKE treatments. Snail overexpression in ARCaP and LNCaP cells was associated with increased concentration of mitochondrial superoxide, in vitro. Interestingly, MSKE decreased superoxide levels in ARCaP and LNCaP cells. Additionally, MSKE and Superoxide Dismutase (SOD) reverted EMT as evidenced by decreased vimentin levels and re-induction of E-cadherin expression in ARCaP-Snail cells after 3 days, concomitant with reduced cell migration. MSKE also decreased Stat-3 activity in ARCaP-Snail cells. This study shows that superoxide species may play a role in Snail transcription factor-mediated EMT. Therefore, therapeutic targeting of Snail with various antioxidants such as MSKE may prove beneficial in abrogating EMT and ROS-mediated tumor progression in human prostate cancer.
    BMC Complementary and Alternative Medicine 03/2014; 14(1):97. DOI:10.1186/1472-6882-14-97 · 2.02 Impact Factor

  • European Urology Supplements 11/2013; 12(6):139. DOI:10.1016/S1569-9056(13)62353-2 · 3.37 Impact Factor
  • Qian Sun · Rebecca S. Arnold · John A. Petros ·

    The Journal of Urology 04/2013; 189(4):e326. DOI:10.1016/j.juro.2013.02.355 · 4.47 Impact Factor

  • The Journal of Urology 04/2013; 189(4):e251. DOI:10.1016/j.juro.2013.02.166 · 4.47 Impact Factor
  • Carrie Q Sun · Rebecca S Arnold · John A Petros ·

    The Journal of Urology 04/2013; 189(4):e473-e474. DOI:10.1016/j.juro.2013.02.795 · 4.47 Impact Factor

  • The Journal of Urology 04/2013; 189(4):e249-e250. DOI:10.1016/j.juro.2013.02.161 · 4.47 Impact Factor
  • Carrie Q Sun · Rebecca S Arnold · John A Petros ·

    The Journal of Urology 04/2013; 189(4):e464. DOI:10.1016/j.juro.2013.02.751 · 4.47 Impact Factor
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    ABSTRACT: Mitochondrial DNA (mtDNA) mutations have been found in many cancers but the physiological derangements caused by such mutations have remained elusive. Prostate cancer is associated with both inherited and somatic mutations in the cytochrome c oxidase (COI) gene. We present a prostate cancer patient-derived rare heteroplasmic mutation of this gene, part of mitochondrial respiratory complex IV. Functional studies indicate that this mutation leads to the simultaneous decrease in cytochrome oxidation, increase in reactive oxygen, and increased reactive nitrogen. These data suggest that mitochondrial DNA mutations resulting in increased reactive oxygen and reactive nitrogen generation may be involved in prostate cancer biology.
    03/2013; 2013(3):239257. DOI:10.1155/2013/239257

  • Cancer Research 06/2012; 72(8 Supplement):5332-5332. DOI:10.1158/1538-7445.AM2012-5332 · 9.33 Impact Factor
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    Takara A Scott · Rebecca S. Arnold · John A Petros ·
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    ABSTRACT: Mitochondrial DNA (mtDNA) gene mutations have been described in nearly every adult solid neoplasm including prostate cancer. There are marked racial differences in specific inherited mutations within the cytochrome c oxidase subunit 1 (COI) gene in individuals with prostate cancer (PCa). The purpose of this study was to identify the variation in COI gene sequence in prostate cancer patients and to compare the mutations in African and Caucasian Americans. We sequenced the COI gene in DNA derived from peripheral blood in 482 prostate cancer patients and 189 controls. All bases that differed from the revised Cambridge Reference Sequence (rCRS) were classified as either silent (non-amino acid altering) or missense (amino acid altering) and the compiled alterations were then compared between races and published reports of mutations in this gene in both Caucasian and African-Americans. We found inherited mtDNA COI missense variants in 8.8% of Caucasian prostate cancer patients (vs. 0.0% controls) and 72.8 % of African-American prostate cancer patients (vs. 64.3% controls) A total of 144 COI variants were identified, of which 30 were missense mutations. Of 482 PCa patients, 116 (24.1%) had one or more missense mutations. Further evaluation of this gene and these mutations may allow for the identification of genetically at-risk populations. The high rate of COI mutations in African-Americans may account for some of the racial disparity observed in prostate cancer.
    05/2012; 2012(4):701810. DOI:10.6064/2012/701810
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    ABSTRACT: [This corrects the article on p. e18272 in vol. 6.].
    PLoS ONE 05/2011; 6(5). DOI:10.1371/annotation/913fdc1e-877e-4c70-ac20-761d2d72400d · 3.23 Impact Factor
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    ABSTRACT: Xenotropic murine leukemia virus-related virus (XMRV) was recently discovered to be the first human gammaretrovirus that is associated with chronic fatigue syndrome and prostate cancer (PC). Although a mechanism for XMRV carcinogenesis is yet to be established, this virus belongs to the family of gammaretroviruses well known for their ability to induce cancer in the infected hosts. Since its original identification XMRV has been detected in several independent investigations; however, at this time significant controversy remains regarding reports of XMRV detection/prevalence in other cohorts and cell type/tissue distribution. The potential risk of human infection, coupled with the lack of knowledge about the basic biology of XMRV, warrants further research, including investigation of adaptive immune responses. To study immunogenicity in vivo, we vaccinated mice with a combination of recombinant vectors expressing codon-optimized sequences of XMRV gag and env genes and virus-like particles (VLP) that had the size and morphology of live infectious XMRV. Immunization elicited Env-specific binding and neutralizing antibodies (NAb) against XMRV in mice. The peak titers for ELISA-binding antibodies and NAb were 1:1024 and 1:464, respectively; however, high ELISA-binding and NAb titers were not sustained and persisted for less than three weeks after immunizations. Vaccine-induced XMRV Env antibody titers were transiently high, but their duration was short. The relatively rapid diminution in antibody levels may in part explain the differing prevalences reported for XMRV in various prostate cancer and chronic fatigue syndrome cohorts. The low level of immunogenicity observed in the present study may be characteristic of a natural XMRV infection in humans.
    PLoS ONE 04/2011; 6(4):e18272. DOI:10.1371/journal.pone.0018272 · 3.23 Impact Factor
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    ABSTRACT: Recent studies demonstrated the importance of ADAM9 in prostate cancer relapse upon therapy. In this study, we determined the role of ADAM9 in the therapeutic resistance to radiation and chemotherapy. ADAM9 was either transiently or stably knocked down in C4-2 prostate cancer cells. The sensitivity of ADAM9 knockdown cells toward radiation and chemotherapeutic agents were determined. Additionally, the effects of ADAM9 knockdown on prostate cancer cell morphology, biochemical and functional alterations were accessed. Both transient and stable knockdown of ADAM9 resulted in increased apoptosis and increased sensitivity to radiation. ADAM9 knockdown also increased prostate cancer sensitivity to several chemotherapeutic drugs. ADAM9 knockdown resulted in increased E-cadherin and altered integrin expression and underwent phenotypic epithelial transition. These were reflected by the morphological, biochemical, and functional alterations in the ADAM9 knockdown cells. ADAM9 plays a crucial role in prostate cancer progression and therapeutic resistance in part by altering E-cadherin and integrin expression. ADAM9 is an important target for the consideration of treating prostate cancer patients who developed therapeutic resistance and disease relapse.
    The Prostate 02/2011; 71(3):232-40. DOI:10.1002/pros.21237 · 3.57 Impact Factor

Publication Stats

3k Citations
267.49 Total Impact Points


  • 1998-2015
    • Emory University
      • • Department of Urology
      • • Department of Pathology and Laboratory Medicine
      • • Department of Biochemistry
      Atlanta, Georgia, United States
  • 2010
    • University of Warsaw
      • Institute of Genetics and Biotechnology
      Warsaw, Masovian Voivodeship, Poland
  • 2006
    • Kagoshima University
      Kagosima, Kagoshima, Japan
    • Duke University
      Durham, North Carolina, United States
  • 2005
    • University of Arkansas at Little Rock
      Little Rock, Arkansas, United States