Valerie Odero-Marah

Clark Atlanta University, Atlanta, Georgia, United States

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Publications (42)206.23 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Snail, a zinc-finger transcription factor, induces epithelial-mesenchymal transition (EMT), which is associated with increased cell migration and metastasis in cancer cells. Rac1 is a small G-protein which upon activation results in formation of lamellipodia, the first protrusions formed by migrating cells. We have previously shown that Snail promotes cell migration through down-regulation of maspin tumor suppressor. We hypothesized that Snail's regulation of cell migration may also involve Rac1 signaling regulated by PI3K/AKT and/or MAPK pathways. We found that Snail overexpression in LNCaP and 22Rv1 prostate cancer cells increased Rac1 activity associated with increased cell migration, and the Rac1 inhibitor, NSC23766, could inhibit Snail-mediated cell migration. Conversely, Snail downregulation using shRNA in the aggressive C4-2 prostate cancer cells decreased Rac1 activity and cell migration. Moreover, Snail overexpression increased ERK and PI3K/AKT activity in 22Rv1 prostate cancer cells. Treatment of Snail-overexpressing 22Rv1 cells with LY294002, PI3K/AKT inhibitor or U0126, MEK inhibitor, decreased cell migration significantly, but only LY294002 significantly reduced Rac1 activity, suggesting that Snail promotes Rac1 activation via the PI3K/AKT pathway. Furthermore, 22Rv1 cells overexpressing Snail displayed decreased maspin levels, while inhibition of maspin expression in 22Rv1 cells with siRNA, led to increased PI3K/AKT, Rac1 activity and cell migration, without affecting ERK activity, suggesting that maspin is upstream of PI3K/AKT. Overall, we have dissected signaling pathways by which Snail may promote cell migration through MAPK signaling or alternatively through PI3K/AKT-Rac1 signaling that involves Snail inhibition of maspin tumor suppressor. This may contribute to prostate cancer progression.
    Cell adhesion & migration 07/2015; 9(4):1-10. DOI:10.1080/19336918.2015.1013383 · 4.51 Impact Factor
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    ABSTRACT: Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology. © The Author 2015. Published by Oxford University Press.
    Carcinogenesis 06/2015; 36(S1):S254–S296. DOI:10.1093/carcin/bgv039 · 5.33 Impact Factor
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    ABSTRACT: To develop new and effective chemopreventive agents against bone metastasis, we assessed the effects of muscadine grape skin extract (MSKE), whose main bioactive component is anthocyanin, on bone turnover, using prostate and breast cancer cell models overexpressing Snail transcription factor. MSKE has been shown previously to promote apoptosis in prostate cancer cells without affecting normal prostate epithelial cells. Snail is overexpressed in prostate and breast cancer, and is associated with increased invasion, migration and bone turnover/osteoclastogenesis. CatL is a cysteine cathepsin protease that is overexpressed in cancer and involved in bone turnover. Snail overexpression in prostate (LNCaP, ARCaP-E) and breast (MCF-7) cancer cells led to increased Cathepsin L (CatL) expression/activity and phosphorylated STAT-3 (pSTAT-3), compared to Neo vector controls, while the reverse was observed in C4-2 (the aggressive subline of LNCaP) cells with Snail knockdown. Moreover, CatL expression was higher in prostate and breast tumor tissue compared to normal tissue. MSKE decreased Snail and pSTAT3 expression, and abrogated Snail-mediated CatL activity, migration and invasion. Additionally, Snail overexpression promoted osteoclastogenesis, which was significantly inhibited by the MSKE as effectively as Z-FY-CHO, a CatL-specific inhibitor, or osteoprotegerin, a receptor activator of nuclear factor kappa B ligand (RANKL) antagonist. Overall, these novel findings suggest that Snail regulation of CatL may occur via STAT-3 signaling and can be antagonized by MSKE, leading to decreased cell invasion, migration and bone turnover. Therefore, inhibition using a natural product such as MSKE could potentially be a promising bioactive compound for bone metastatic cancer. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email:
    Carcinogenesis 06/2015; 36(9). DOI:10.1093/carcin/bgv084 · 5.33 Impact Factor
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    ABSTRACT: The purpose of this review is to stimulate new ideas regarding low-dose environmental mixtures and carcinogens and their potential to promote invasion and metastasis. Whereas a number of chapters in this review are devoted to the role of low-dose environmental mixtures and carcinogens in the promotion of invasion and metastasis in specific tumors such as breast and prostate, the overarching theme is the role of low-dose carcinogens in the progression of cancer stem cells. It is becoming clearer that cancer stem cells in a tumor are the ones that assume invasive properties and colonize distant organs. Therefore, low-dose contaminants that trigger epithelial–mesenchymal transition, for example, in these cells are of particular interest in this review. This we hope will lead to the collaboration between scientists who have dedicated their professional life to the study of carcinogens and those whose interests are exclusively in the arena of tissue invasion and metastasis.
    Carcinogenesis 06/2015; 36(Suppl 1):S128-S159. DOI:10.1093/carcin/bgv034 · 5.33 Impact Factor

  • Cancer Epidemiology Biomarkers & Prevention 11/2014; 23(11 Supplement):C60-C60. DOI:10.1158/1538-7755.DISP13-C60 · 4.13 Impact Factor
  • Liza Burton · Peri Nappagan · Basil Smith · Manu Platt · Camille Ragin · Valerie Odero-Marah ·

    Cancer Epidemiology Biomarkers & Prevention 11/2014; 23(11 Supplement):C57-C57. DOI:10.1158/1538-7755.DISP13-C57 · 4.13 Impact Factor
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    ABSTRACT: Metastatic prostate cancer (mPCa) relapses after a short period of androgen deprivation therapy and becomes the castration-resistant prostate cancer (CR PCa); to which the treatment is limited. Hence, it is imperative to identify novel therapeutic agents towards this patient population. In the present study, antiproliferative activities of novel imidazopyridines were compared. Among three derivatives, PHE, AMD and AMN, examined, AMD showed the highest inhibitory activity on LNCaP C-81 cell proliferation, following dose- and time-dependent manner. Additionally, AMD exhibited significant antiproliferative effect against a panel of PCa cells, but not normal prostate epithelial cells. Further, when compared to AMD, its derivative DME showed higher inhibitory activities on PCa cell proliferation, clonogenic potential and in vitro tumorigenicity. The inhibitory activity was apparently in part due to the induction of apoptosis. Mechanistic studies indicate that AMD and DME treatments inhibited both AR and PI3K/Akt signaling. The results suggest that better understanding of inhibitory mechanisms of AMD and DME could help design novel therapeutic agents for improving the treatment of CR PCa.
    Cancer Letters 10/2014; 353(1). DOI:10.1016/j.canlet.2014.07.002 · 5.62 Impact Factor

  • Cancer Research 10/2014; 74(19 Supplement):1131-1131. DOI:10.1158/1538-7445.AM2014-1131 · 9.33 Impact Factor
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    ABSTRACT: Snail transcription factor is up-regulated in several cancers and associated with increased tumor migration and invasion via induction of epithelial-to-mesenchymal transition (EMT). MAPK (ERK1/2) signaling regulates cellular processes including cell motility, adhesion, and invasion. We investigated the regulation of ERK1/2 by Snail in breast cancer cells. ERK1/2 activity (p-ERK) was higher in breast cancer patient tissue as compared to normal tissue. Snail and p-ERK were increased in several breast cancer cell lines as compared to normal mammary epithelial cells. Snail knockdown in MDA-MB-231 and T47-D breast cancer cells decreased or re-localized p-ERK from the nuclear compartment to the cytoplasm. Snail overexpression in MCF-7 breast cancer cells induced EMT, increased cell migration, decreased cell adhesion and also increased tumorigenicity. Snail induced nuclear translocation of p-ERK, and the activation of its subcellular downstream effector, Elk-1. Inhibiting MAPK activity with UO126 or knockdown of ERK2 isoform with siRNA in MCF-7 Snail cells reverted EMT induced by Snail as shown by decreased Snail and vimentin expression, decreased cell migration and increased cell adhesion. Overall, our data suggest that ERK2 isoform activation by Snail in aggressive breast cancer cells leads to EMT associated with increased cell migration and decreased cell adhesion. This regulation is enhanced by positive feedback regulation of Snail by ERK2. Therefore, therapeutic targeting of ERK2 isoform may be beneficial for breast cancer.
    PLoS ONE 08/2014; 9(8):e104987. DOI:10.1371/journal.pone.0104987 · 3.23 Impact Factor
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    ABSTRACT: Camalexin, the phytoalexin produced in the model plant Arabidopsis thaliana, possesses antiproliferative and cancer chemopreventive effects. We have demonstrated that the cytostatic/cytotoxic effects of camalexin on several prostate cancer (PCa) cells are due to oxidative stress. Lysosomes are vulnerable organelles to Reactive Oxygen Species (ROS)-induced injuries, with the potential to initiate and or facilitate apoptosis subsequent to release of proteases such as cathepsin D (CD) into the cytosol. We therefore hypothesized that camalexin reduces cell viability in PCa cells via alterations in expression and activity of CD. Cell viability was evaluated by MTS cell proliferation assay in LNCaP and ARCaP Epithelial (E) cells, and their respective aggressive sublines C4-2 and ARCaP Mesenchymal (M) cells, whereby the more aggressive PCa cells (C4-2 and ARCaPM) displayed greater sensitivity to camalexin treatments than the lesser aggressive cells (LNCaP and ARCaPE). Immunocytochemical analysis revealed CD relocalization from the lysosome to the cytosol subsequent to camalexin treatments, which was associated with increased protein expression of mature CD; p53, a transcriptional activator of CD; BAX, a downstream effector of CD, and cleaved PARP, a hallmark for apoptosis. Therefore, camalexin reduces cell viability via CD and may present as a novel therapeutic agent for treatment of metastatic prostate cancer cells.
    Molecules 04/2014; 19(4):3988-4005. DOI:10.3390/molecules19043988 · 2.42 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
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    ABSTRACT: Reactive oxygen species (ROS) are implicated in many human diseases, including cancer. We have previously demonstrated that ROS increased the expression and activity of the chemokine receptor, CXCR4, which enhanced metastatic functions in prostate cancer cells. Studies have also revealed that CXCR4 and its ligand, SDF-1α, promoted ROS accumulation; however the source of ROS was not investigated. Recent evidence suggested that ROS accumulation in prostate cancer cell lines was contributed by the NADPH oxidase (NOX) family of enzymes. Herein, we sought to determine whether the CXCR4/SDF-1α signaling axis mediates ROS production through NOX in prostate cancer. We observed an increase in intracellular ROS generation in prostate cancer cells upon SDF-1α stimulation compared to untreated samples. Conversely, lower levels of ROS were detected in cells treated with AMD3100 (CXCR4 antagonist) or the ROS scavenger, N-acetyl-cysteine (NAC). Markedly reduced levels of ROS were observed in cells treated with apocynin (NOX inhibitor) compared to rotenone (mitochondrial complex I inhibitor)-treated cells. Specifically, we determined that NOX2 responded to, and was regulated by, the SDF-1α/CXCR4 signaling axis. Moreover, chemical inhibition of the ERK1/2 and PI3K pathways revealed that PI3K/AKT signaling participated in CXCR4-mediated NOX activity, and that these collective signaling events resulted in enhanced cell movement towards a chemoattractant. Finally, NOX2 may be a potential therapeutic target, as Oncomine microarray database analysis of normal prostate, benign prostatic hyperplasia (BPH) and prostatic intraepithelial neoplasia (PIN) tissue samples determined a correlation between NOX2 expression and prostate cancer. Taken together, these results suggest that CXCR4/SDF-1α-mediated ROS production through NOX2 enzymes may be an emerging concept by which chemokine signaling progresses tumorigenesis.
    Cancer Microenvironment 09/2013; 6(3). DOI:10.1007/s12307-013-0136-0

  • Cancer Research 08/2013; 73(8 Supplement):1485-1485. DOI:10.1158/1538-7445.AM2013-1485 · 9.33 Impact Factor
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    ABSTRACT: Reactive oxygen species (ROS) play a central role in oxidative stress, which leads to the onset of diseases, such as cancer. Furthermore, ROS contributes to the delicate balance between tumor cell survival and death. However, the mechanisms by which tumor cells decide to elicit survival or death signals during oxidative stress are not completely understood. We have previously reported that ROS enhanced tumorigenic functions in prostate cancer cells, such as transendothelial migration and invasion, which depended on CXCR4 and AKT signaling. Here, we report a novel mechanism by which ROS facilitated cell death through activation of AKT. We initially observed that ROS enhanced the expression of phosphorylated AKT (p-AKT) in 22Rv1 human prostate cancer cells. The tumor suppressor PTEN, a negative regulator of AKT signaling, was rendered catalytically inactive through oxidation by ROS, although the expression levels remained consistent. Despite these events, cells still underwent apoptosis. Further investigation into apoptosis revealed that expression of the tumor suppressor pVHL increased, and contains a target site for p-AKT phosphorylation. pVHL and p-AKT associated in vitro, and knockdown of pVHL rescued HIF1α expression and the cells from apoptosis. Collectively, our study suggests that in the context of oxidative stress, p-AKT facilitated apoptosis by inducing pVHL function.
    Molecular and Cellular Biochemistry 01/2013; 376(1-2). DOI:10.1007/s11010-012-1549-7 · 2.39 Impact Factor
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    ABSTRACT: Camalexin is a phytoalexin that accumulates in various cruciferous plants upon exposure to environmental stress and plant pathogens. Besides moderate antibacterial and antifungal activity, camalexin was reported to also exhibit antiproliferative and cancer chemopreventive effects in breast cancer and leukemia. We studied the cytotoxic effects of camalexin treatment on prostate cancer cell lines and whether this was mediated by reactive oxygen species (ROS) generation. As models, we utilized LNCaP and its aggressive subline, C4-2, as well as ARCaP cells stably transfected with empty vector (Neo) control or constitutively active Snail cDNA that represents an epithelial to mesenchymal transition (EMT) model and displays increased cell migration and tumorigenicity. We confirmed previous studies showing that C4-2 and ARCaP-Snail cells express more ROS than LNCaP and ARCaP-Neo, respectively. Camalexin increased ROS, decreased cell proliferation, and increased apoptosis more significantly in C4-2 and ARCaP-Snail cells as compared to LNCaP and ARCaP-Neo cells, respectively, while normal prostate epithelial cells (PrEC) were unaffected. Increased caspase-3/7 activity and increased cleaved PARP protein shown by Western blot analysis was suggestive of increased apoptosis. The ROS scavenger N-acetyl cysteine (NAC) antagonized the effects of camalexin, whereas the addition of exogenous hydrogen peroxide potentiated the effects of camalexin, showing that camalexin is mediating its effects through ROS. In conclusion, camalexin is more potent in aggressive prostate cancer cells that express high ROS levels, and this phytoalexin has a strong potential as a novel therapeutic agent for the treatment of especially metastatic prostate cancer.
    Journal of Natural Medicines 11/2012; 67(3). DOI:10.1007/s11418-012-0722-3 · 1.59 Impact Factor
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    Bethany N Smith · Valerie A Odero-Marah ·
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    ABSTRACT: Prostate cancer is the second most frequently diagnosed cancer and the sixth leading cause of death from cancer in men. Epithelial-mesenchymal transition (EMT) is a process by which cancer cells invade and migrate, and is characterized by loss of cell-cell adhesion molecules such as E-cadherin and increased expression of mesenchymal proteins such as vimentin; EMT is also associated with resistance to therapy. Snail, a master regulator of EMT, has been extensively studied and reported in cancers such as breast and colon, however, its role in prostate cancer is not as widely reported. The purpose of this review is to put together recent facts that summarize Snail signaling in human prostate cancer. Snail is overexpressed in prostate cancer and its expression and activity is controlled via phosphorylation and growth factor signaling. Snail is involved in its canonical role of inducing EMT in prostate cancer cells; however, it plays a role in non-canonical pathways that do not involve EMT such regulation of bone turnover and neuroendocrine differentiation. Thus, studies indicate that Snail signaling contributes to prostate cancer progression and metastasis and therapeutic targeting of Snail in prostate cancer holds promise in future.
    Cell adhesion & migration 09/2012; 6(5). DOI:10.4161/cam.21687 · 4.51 Impact Factor
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    ABSTRACT: Maspin, a putative tumor suppressor that is down-regulated in breast and prostate cancer, has been associated with decreased cell motility. Snail transcription factor is a zinc finger protein that is increased in breast cancer and is associated with increased tumor motility and invasion by induction of epithelial-mesenchymal transition (EMT). We investigated the molecular mechanisms by which Snail increases tumor motility and invasion utilizing prostate cancer cells. Expression levels were analyzed by RT-PCR and western blot analyses. Cell motility and invasion assays were performed, while Snail regulation and binding to maspin promoter was analyzed by luciferase reporter and chromatin immunoprecipitation (ChIP) assays. Snail protein expression was higher in different prostate cancer cells lines as compared to normal prostate epithelial cells, which correlated inversely with maspin expression. Snail overexpression in 22Rv1 prostate cancer cells inhibited maspin expression and led to increased migration and invasion. Knockdown of Snail in DU145 and C4-2 cancer cells resulted in up-regulation of maspin expression, concomitant with decreased migration. Transfection of Snail into 22Rv1 or LNCaP cells inhibited maspin promoter activity, while stable knockdown of Snail in C4-2 cells increased promoter activity. ChIP analysis showed that Snail is recruited to the maspin promoter in 22Rv1 cells. Overall, this is the first report showing that Snail can negatively regulate maspin expression by directly repressing maspin promoter activity, leading to increased cell migration and invasion. Therefore, therapeutic targeting of Snail may be useful to re-induce expression of maspin tumor suppressor and prevent prostate cancer tumor progression.
    BMC Cancer 08/2012; 12(1):336. DOI:10.1186/1471-2407-12-336 · 3.36 Impact Factor

  • Cancer Research 06/2012; 72(8 Supplement):5747-5747. DOI:10.1158/1538-7445.AM2012-5747 · 9.33 Impact Factor

  • Cancer Research 06/2012; 72(8 Supplement):5332-5332. DOI:10.1158/1538-7445.AM2012-5332 · 9.33 Impact Factor
  • Diandra D. Randle · Shineka Clarke · Valerie Odero-Marah ·

    Cancer Research 04/2012; 72(8 Supplement):2407-2407. DOI:10.1158/1538-7445.AM2012-2407 · 9.33 Impact Factor

Publication Stats

806 Citations
206.23 Total Impact Points


  • 2008-2014
    • Clark Atlanta University
      • • Department of Biological Sciences
      • • Center for Cancer Research and Therapeutic Development
      Atlanta, Georgia, United States
  • 2010
    • Georgia Institute of Technology
      • School of Biology
      Atlanta, Georgia, United States
  • 2004-2009
    • Emory University
      • Department of Urology
      Atlanta, Georgia, United States
  • 2002-2005
    • University of Iowa
      • Department of Anatomy and Cell Biology
      Iowa City, Iowa, United States