Shadan Ali

Karmanos Cancer Institute, Detroit, Michigan, United States

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Publications (77)360.91 Total impact

  • Journal of the American Society of Cytopathology. 10/2014; 3(5):S5–S6.
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    ABSTRACT: Metformin is one of the most used diabetic drugs for the management of type II diabetes mellitus (DM) in the world. Increased numbers of epidemiological and clinical studies have provided convincing evidence supporting the role of metformin in the development and progression of a variety of human tumors including breast and pancreatic cancer. Substantial pre-clinical evidence from in vitro and in vivo experimental studies strongly suggests that metformin has an anti-cancer activity mediated through the regulation of several cell signaling pathways including activation of AMP kinase (AMPK), and other direct and indirect mechanisms; however, the detailed mechanism(s) has not yet been fully understood. The concept of cancer stem cells (CSCs) has gained significant attention in recent years due its identification and defining its clinical implications in many different tumors including breast cancer and pancreatic cancer. In this review, we will discuss the protective role of metformin in the development of breast and pancreatic cancers. We will further discuss the role of metformin as an anti-cancer agent, which is in part mediated through targeting CSCs. Finally, we will discuss the potential role of metformin in the modulation of tumor-associated or CSC-associated microRNAs (miRNAs) as part of the novel mechanism of action of metformin in the development and progression of breast and pancreatic cancers.
    Annals of translational medicine. 06/2014; 2(6):59.
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    ABSTRACT: Aberrant expression of microRNAs (miRNAs) plays important roles in the development and progression of pancreatic cancer (PC). Expression analysis of miR-146a in human PC tissues showed decreased expression in about 80% of samples compared to corresponding non-cancerous tissue. Moreover, expression of miR-146a in eight PC cell lines, and in pancreatic tissues obtained from transgenic mouse models of K-Ras (K), Pdx1-Cre (C), K-Ras;Pdx1-Cre (KC) and K-Ras;Pdx1-Cre;INK4a/Arf (KCI), showed down-regulation of miR-146a expression in KCI mice which was in part led to over-expression of its target gene, epidermal growth factor receptor (EGFR). Treatment of PC cells with CDF, a novel synthetic compound, led to re-expression of miR-146a, resulting in the down-regulation of EGFR expression. Moreover, re-expression of miR-146a by stable transfection or treatment with CDF in vivo (xenograft animal model) resulted in decreased tumor growth which was consistent with reduced EGFR, ERK1, ERK2, and K-Ras expression. Further knock-down of miR-146a in AsPC-1 cells led to the up-regulation of EGFR expression and showed increased clonogenic growth. In addition, knock-down of EGFR by EGFR siRNA transfection of parental AsPC-1 cells and AsPC-1 cells stably transfected with pre-miR-146a resulted in decreased invasive capacity, which was further confirmed by reduced luciferase activity in cells transfected with pMIR-Luc reporter vector containing miR-146a binding site. Collectively, these results suggest that the loss of expression of miR-146a is a fundamental mechanism for over-expression of EGFR signaling and that re-expression of miR-146a by CDF treatment could be useful in designing personalized strategy for the treatment of human PC.
    Cancer Letters 05/2014; · 5.02 Impact Factor
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    ABSTRACT: Pancreatic cancer (PC) is one of the most deadly cancers. The higher mortality is in part due to treatment resistance and early onset of metastasis. The existence of cancer stem like cells (CSLCs) has been widely accepted to be responsible for tumor aggressiveness in PC. Emerging evidence suggests that CSLCs have the capacity for increased cell growth, cell migration/invasion, metastasis, and treatment resistance, which leads to poor clinical outcome. However, the molecular role of CSLCs in tumor development and progression is poorly understood. Therefore, mechanistic understanding, and targeted killing of CSLCs may provide a newer therapeutic strategy for the treatment of PC. It has been well accepted that microRNAs (miRNAs) play critical roles during tumor development and progression through deregulation of multiple genes. Moreover, deregulated expression of miRNAs may also play a key role in the regulation of CSLCs characteristics and functions. Here we show that isolated CD44+/CD133+/EpCAM+ cells (triple-positive cells) from human PC cell lines, MiaPaCa-2 and L3.6pl cells display aggressive characteristics such as increased cell growth, clonogenicity, cell migration, and self-renewal capacity, which is consistent with over-expression of CSLC signatures/markers. We also found deregulated expression of over 400 miRNAs including let-7, miR-30, miR-125b, and miR-335 in CSLCs. As a proof-of-concept, knockdown of miR-125b resulted in the inhibition of tumor cell aggressiveness of CSLCs (triple-positive cells), consistent with the down-regulation of CD44, EpCAM, EZH2, and snail. These results clearly suggest the importance of miRNAs in the regulation of CSLCs characteristics, and may serve as novel targets for therapy.
    Stem cells and development 04/2014; · 4.15 Impact Factor
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    ABSTRACT: Sub-populations of cancer stem cells (CSCs) or cancer stem-like cells (CSLCs) have been identified from most tumors including pancreatic cancer (PC), and the existence of these cells is clinically relevant. Emerging evidence suggests that CSLCs participate in cell growth/proliferation, migration/invasion, metastasis, and chemo-radio-therapy resistance, ultimately contributing to poor clinical outcome. However, the pathogenesis and biological significance of CSLCs in PC has not been well characterized. In the present study, we found that isolated triple-marker positive (CD44+/CD133+/EpCAM+) cells of human PC MiaPaCa-2 and L3.6pl cells behave as CSLCs. These CSLCs exhibit aggressive behavior such as increased cell growth, migration, clonogenicity, and self-renewal capacity. The mRNA expression profiling analysis showed that CSLCs (CD44+/CD133+/EpCAM+) exhibit differential expression of more than 1600 mRNAs including FoxQ1, compared to the triple-marker negative (CD44-/CD133-/EpCAM-) cells. The knock-down of FoxQ1 by its siRNA in CSLCs resulted in the inhibition of aggressive behavior, consistent with the inhibition of EpCAM and snail expression. Mouse xenograft tumor studies showed that CSLCs have a 100-fold higher potential for tumor formation and rapid tumor growth, consistent with over-expression of CSC-associated markers/mediators including FoxQ1, compared to its parental MiaPaCa-2 cells. The inhibition of FoxQ1 attenuated tumor formation and growth, and expression of CSC markers in the xenograft tumor derived from CSLCs of MiaPaCa-2 cells. These data clearly suggesting the role of differentially expressed genes in the regulation of CSLC characteristics, further suggesting that targeting some of these genes could be important for the development of novel therapies for achieving better treatment outcome of PC.
    Journal of Biological Chemistry 04/2014; · 4.60 Impact Factor
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    ABSTRACT: MicroRNAs (miRNAs) are small endogenous non-coding single-stranded RNAs. They critically regulate the post-transcriptional activity of several key physiological and pathological cell processes including cancer. Through their transcriptional regulatory functions, miRNAs control tumor proliferation, invasion and metastasis. The expression of miRNAs is altered in malignancies. It could be either up or down-regulated depending upon the role of a particular miRNA in the pathogenetic development of the tumor. The up-regulated miRNAs exert an ‘oncogenic’ effect leading to tumor proliferation and metastasis. The down-regulated miRNAs have ‘tumor suppressor’ effects. Recent studies have demonstrated that miRNAs have a role in the early diagnosis, prognosis and treatment outcome assessment of cancers. Every tumor has specific miRNA alterations i.e. some are over expressed and others are down-regulated. These altered miRNAs can be used as a tumor specific 'signature' for potential clinical use in improving accuracy of diagnosis, determining prognosis and as therapeutic targets for therapy. Specific miRNAs can be targeted using oligonucleotide sequences corresponding to the altered miRNAs. These are referred to as ‘antagomirs’. Depending upon the miRNA alterations in the tumor of an individual patient, one could design targeted therapies for personalized medicine in patients. Hence miRNAs have an immense role in personalized cancer therapy.
    Clinical Genetics 02/2014; · 3.65 Impact Factor
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    ABSTRACT: MicroRNAs are small endogenous noncoding RNAs that are critical regulators of several physiologic and pathologic processes including cancers. Variations in the level of microRNA expression have been linked with the development, progression, and spread of cancer to distant organs. These tiny molecules may play a role in accurate and early diagnosis, and also as prognostic determinants. Modulating their activity provides opportunities for developing and designing novel cancer therapeutics. Recent studies indicate their detection in a wide variety of human biologic specimens including blood, serum, fine-needle aspirates, and tissues, making them clinically useful biomarkers of disease for early detection, prognosis, and for designing personalized therapies.
    Clinics in laboratory medicine 12/2013; 33(4):773-786. · 1.17 Impact Factor
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    ABSTRACT: Prostate Cancer (PCa) is the second leading cause of cancer death in men. Current research findings suggest that the androgen receptor (AR) and its signaling pathway contribute significantly to the progression of metastatic PCa. The AR is a ligand activated transcription factor, where androgens such as testosterone (T) and dihydroxytestosterone (DHT) act as the activating ligands. However in many metastatic PCa, the AR functions promiscuously and is constitutively active through multiple mechanisms. Inhibition of enzymes that take part in androgen synthesis or synthesizing antiandrogens that can inhibit the AR are two popular methods of impeding the androgen receptor signaling axis; however, the inhibition of androgen-independent activated AR function has not yet been fully exploited. This article focuses on the development of emerging novel agents that act at different steps along the androgen-AR signaling pathway to help improve the poor prognosis of PCa patients. J. Cell. Physiol. © 2013 Wiley Periodicals, Inc.
    Journal of Cellular Physiology 08/2013; 229(3). · 3.87 Impact Factor
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    ABSTRACT: Reactive oxygen species (ROS) have been widely considered as critical cellular signaling molecules involving in various biological processes such as cell growth, differentiation, proliferation, apoptosis, and angiogenesis. The homeostasis of ROS is critical to maintain normal biological processes. Increased production of ROS, namely oxidative stress, due to either endogenous or exogenous sources causes irreversible damage of bio-molecules such as DNA, proteins, lipids, and sugars, leading to genomic instability, genetic mutation, and altered gene expression, eventually contributing to tumorigenesis. A great amount of experimental studies in vitro and in vivo have produced solid evidence supporting that oxidative stress is strongly associated with increased tumor cell growth, treatment resistance, and metastasis, and all of which contribute to tumor aggressiveness. More recently, the data have indicated that altered production of ROS is also associated with cancer stem cells (CSCs), epithelial-to-mesenchymal transition (EMT), and hypoxia, the most common features or phenomena in tumorigenesis and tumor progression. However, the exact mechanism by which ROS is involved in the regulation of CSC and EMT characteristics as well as hypoxia- and, especially, HIF-mediated pathways is not well known. Emerging evidence suggests the role of miRNAs in tumorigenesis and progression of human tumors. Recently, the data have indicated that altered productions of ROS are associated with deregulated expression of miRNAs, suggesting their potential roles in the regulation of ROS production. Therefore, targeting ROS mediated through the deregulation of miRNAs by novel approaches or by naturally occurring anti-oxidant agents such as genistein could provide a new therapeutic approach for the prevention and/or treatment of human malignancies.
    Current Stem Cell Research & Therapy 08/2013; · 2.86 Impact Factor
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    ABSTRACT: Isoflavones have been investigated in detail for their role in the prevention and therapy of prostate cancer. This is primarily because of the overwhelming data connecting high dietary isoflavone intake with reduced risk of developing prostate cancer. A number of investigations have evaluated the mechanism(s) of anticancer action of isoflavones such as genistein, daidzein, biochanin A, equol, etc., in various prostate cancer models, both in vitro and in vivo. Genistein quickly jumped to the forefront of isoflavone cancer research, but the initial enthusiasm was followed by reports on its contradictory prometastatic and tumor-promoting effects. Use of soy isoflavone mixture has been advocated as an alternative, wherein daidzein can negate harmful effects of genistein. Recent research indicates a novel role of genistein and other isoflavones in the potentiation of radiation therapy, epigenetic regulation of key tumor suppressors and oncogenes, and the modulation of miRNAs, epithelial-to-mesenchymal transition, and cancer stem cells, which has renewed the interest of cancer researchers in this class of anticancer compounds. This comprehensive review article summarizes our current understanding of the role of isoflavones in prostate cancer research.
    The AAPS Journal 07/2013; · 3.91 Impact Factor
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    ABSTRACT: Cancer diagnosis is currently undergoing a paradigm shift with the incorporation of molecular biomarkers as part of routine diagnostic panel. The molecular alteration ranges from those involving the DNA, RNA, microRNAs (miRNAs) and proteins. The miRNAs are recently discovered small non-coding endogenous single-stranded RNAs that critically regulates the development, invasion and metastasis of cancers. They are altered in cancers and have the potential to serve as diagnostic markers for cancer. Moreover, deregulating their activity offers novel cancer therapeutic approaches. The availability of high throughput techniques for the identification of altered cellular molecules allowed their use in cancer diagnosis. Their application to a variety of body specimens from blood to tissues has been helpful for appreciating their use in the clinical context. The development of innovative antibodies for immunohistochemical detection of proteins also assists in diagnosis and risk stratification. Overall, the novel cancer diagnostic tools have extended their application as prognostic risk factors and can be used as targets for personalized medicine.
    International Journal of Molecular Sciences 07/2013; 14(7):14771-84. · 2.34 Impact Factor
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    ABSTRACT: The identification of small subpopulations of cancer stem cells (CSCs) from blood mononuclear cells in human acute myeloid leukemia (AML) in 1997 was a landmark observation that recognized the potential role of CSCs in tumor aggressiveness. Two critical properties contribute to the functional role of CSCs in the establishment and recurrence of cancerous tumors: their capacity for self-renewal and their potential to differentiate into unlimited heterogeneous populations of cancer cells. These findings suggest that CSCs may represent novel therapeutic targets for the treatment and/or prevention of tumor progression, since they appear to be involved in cell migration, invasion, metastasis, and treatment resistance-all of which lead to poor clinical outcomes. The identification of CSC-specific markers, the isolation and characterization of CSCs from malignant tissues, and targeting strategies for the destruction of CSCs provide a novel opportunity for cancer research. This overview describes the potential implications of several common CSC markers in the identification of CSC subpopulations that are restricted to common malignant diseases, e.g., leukemia, and breast, prostate, pancreatic, and lung cancers. The role of microRNAs (miRNAs) in the regulation of CSC function is also discussed, as are several methods commonly used in CSC research. The potential role of the antidiabetic drug metformin- which has been shown to have effects on CSCs, and is known to function as an antitumor agent-is discussed as an example of this new class of chemotherapeutics.Curr. Protoc. Pharmacol. 61:14.25.1-14.25.14 © 2013 by John Wiley & Sons, Inc.
    Current protocols in pharmacology 06/2013; Chapter 14:Unit14.25.
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    ABSTRACT: Herceptin failure is a major clinical problem in breast cancer. A subset of breast cancer patients with high HER-2/neu levels eventually experience metastatic disease progression when treated with Herceptin as a single agent. Mechanistic details of development of this aggressive disease are not clear. Therefore, there is a dire need to better understand the mechanisms by which drug resistance develops and to design new combined treatments that benefit patients with aggressive breast cancer and have minimal toxicity. We hypothesized that 3, 3'-diindolylmethane (DIM), a non-toxic agent can be combined with Herceptin to treat breast cancers with high levels of HER-2/neu. Here, we evaluated the effects of Herceptin alone and in combination with DIM on cell viability, apoptosis and clonogenic assays in SKBR3 (HER-2/neu-expressing) and MDA-MB-468 (HER-2/neu negative) breast cancer cells. We found that DIM could enhance the effectiveness of Herceptin by significantly reducing cell viability, which was associated with apoptosis-induction and significant inhibition of colony formation, compared with single agent treatment. These results were consistent with the down-regulation of Akt and NF-kB p65. Mechanistic investigations revealed a significant upregulation of miR-200 and reduction of FoxM1 expression in DIM and Herceptin-treated breast cancer cells. We, therefore, transfected cells with pre-miR-200 or silenced FoxM1 in these cells for understanding the molecular mechanism involved. These results provide experimental evidence, for the first time, that DIM plus Herceptin therapy could be translated to the clinic as a therapeutic modality to improve treatment outcome of patients with breast cancer, particularly for the patients whose tumors express high levels of HER-2/neu.
    PLoS ONE 01/2013; 8(1):e54657. · 3.53 Impact Factor
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    ABSTRACT: BACKGROUND: Alterations in microRNA (miRNA/miR) genes are of biological importance in the pathophysiology of cancers, including pancreatic cancer (PaCa). Although growing evidence supports the role of miRNA in cancer, their response to dietary phytochemicals is less known. Previously, we showed that garcinol induces PaCa cell growth arrest and apoptosis in vitro. The present study, discusses chemo-sensitization by garcinol in synergism with first-line PaCa drug, gemcitabine. The miRNA expression profile of gemcitabine-resistant Panc-1 cells treated with garcinol and/or gemcitabine was also evaluated. METHODS AND RESULTS: Garcinol synergizes with gemcitabine to inhibit cell proliferation and induce apoptosis in PaCa cells with significant modulation of key cancer regulators including PARP, VEGF, MMPs, ILs, caspases, and NF-κB. In addition, biostatistical analyses, quantitative reverse transcription PCR data, and in silico modeling using TargetScan5, PicTar, and DNA intelligent analysis, microT-V.B4 database showed that these two agents modulated a number of microRNAs (miR-21, miR-196a, miR-495, miR-605, miR-638, and miR-453) linked to various canonical oncogenic signaling pathways. CONCLUSION: We identified garcinol-specific miRNA biomarkers that sensitize PaCa cells to gemcitabine treatment, thus attenuating the drug-resistance phenotype. These results prompt further interest in garcinol and gemcitabine combination strategy as a drug modality to improve treatment outcome in patients diagnosed with PaCa.
    Molecular Nutrition & Food Research 01/2013; · 4.91 Impact Factor
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    ABSTRACT: Pancreatic cancer is the fourth leading cause of cancer related death in the US and exhibits aggressive features with short survival rate and high mortality. Therefore, it is important to understand the molecular mechanism(s) involved in the aggressive growth of pancreatic cancers, and further design novel targeted therapies for its treatment with better treatment outcome. In the present study, we found that the expression of miR-221 was significantly up-regulated in pancreatic cancer cell lines and tumor tissues compared to normal pancreatic duct epithelial cells and normal pancreas tissues. Moreover, we found that the pancreatic cancer patients with high miR-221 expression had a relatively shorter survival compared to those with lower expression, suggesting that miR-221 could be an oncogenic miRNA and a prognostic factor for poor survival of patients. Interestingly, transfection of miR-221 inhibitor suppressed the proliferative capacity of pancreatic cancer cells with concomitant up-regulation of PTEN, p27(kip1), p57(kip2), and PUMA, which are the tumor suppressors and the predicted targets of miR-221. Most importantly, we found that the treatment of pancreatic cancer cells with isoflavone mixture (G2535), formulated 3,3'-diindolylmethane (BR-DIM), or synthetic curcumin analogue (CDF) could down-regulate the expression of miR-221 and consequently up-regulate the expression of PTEN, p27(kip1), p57(kip2), and PUMA, leading to the inhibition of cell proliferation and migration of MiaPaCa-2 and Panc-1 cells. These results provide experimental evidence in support of the oncogenic role of miR-221 and also demonstrate the role of isoflavone, BR-DIM, and CDF as potential non-toxic agents that are capable of down-regulation of miR-221. Therefore, these agents combined with conventional chemotherapeutics could be useful in designing novel targeted therapeutic strategy for the treatment of pancreatic cancer for which there is no curative therapy.
    American Journal of Cancer Research 01/2013; 3(5):465-77. · 3.97 Impact Factor
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    ABSTRACT: Hypoxia is known to play critical roles in cell survival, angiogenesis, tumor invasion, and metastasis. Hypoxia mediated over-expression of hypoxia-inducible factor (HIF) has been shown to be associated with therapeutic resistance, and contributes to poor prognosis of cancer patients. Emerging evidence suggest that hypoxia and HIF pathways contributes to the acquisition of epithelial-to-mesenchymal transition (EMT), maintenance of cancer stem cell (CSC) functions, and also maintains the vicious cycle of inflammation-all which lead to therapeutic resistance. However, the precise molecular mechanism(s) by which hypoxia/HIF drives these events are not fully understood. Here, we show, for the first time, that hypoxia leads to increased expression of VEGF, IL-6, and CSC signature genes Nanog, Oct4 and EZH2 consistent with increased cell migration/invasion and angiogenesis, and the formation of pancreatospheres, concomitant with increased expression of miR-21 and miR-210 in human pancreatic cancer (PC) cells. The treatment of PC cells with CDF, a novel synthetic compound inhibited the production of VEGF and IL-6, and down-regulated the expression of Nanog, Oct4, EZH2 mRNAs, as well as miR-21 and miR-210 under hypoxia. CDF also led to decreased cell migration/invasion, angiogenesis, and formation of pancreatospheres under hypoxia. Moreover, CDF decreased gene expression of miR-21, miR-210, IL-6, HIF-1α, VEGF, and CSC signatures in vivo in a mouse orthotopic model of human PC. Collectively, these results suggest that the anti-tumor activity of CDF is in part mediated through deregulation of tumor hypoxic pathways, and thus CDF could become a novel, and effective anti-tumor agent for PC therapy.
    PLoS ONE 12/2012; 7(12):e50165. · 3.53 Impact Factor
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    ABSTRACT: Cancer epidemiology and prevention is one of the most well studied fields today. The more we can understand about the incidence and pathogenesis of this disease, the better we will be able to prevent it. Effective prevention strategies can decrease the mortality rate of cancer significantly; this is why it is important to delineate the underlying causes. It has been well recognized that genetic mutations, sporadic or hereditary, may lead to increased chance of tumorigenesis. Detecting genetic mutations can lead to the identification of high-risk individuals with hereditary cancer syndromes, which may assist in devising prevention strategies. Further, environmental factors are known to play important roles in epidemiology and suggest prevention tools that could be implemented to reduce cancer incidence and subsequent cancer-associated morbidity and mortality. Chemoprevention has been tried in colon cancer and is finding new advancements in other carcinomas as well. Out of many environmental cancer preventive agents, the most notable developments are the identification of the role of vitamins E, vitamin D and folic acid. Increased consumption of these vitamins has shown to be inversely correlated with cancer risk. This review will highlight important aspects of cancer epidemiology in the most aggressive carcinomas of the gastrointestinal system focusing on colorectal adenocarcinoma and pancreatic adenocarcinoma. Additionally, some of the well-known and evolving aspects of epidemiology of colorectal and pancreatic cancer along with current and new prevention strategies will also be reviewed.
    International Journal of Molecular Sciences 12/2012; 13(10):12556-72. · 2.34 Impact Factor
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    ABSTRACT: The theory of cancer stem cells (CSCs) has provided evidence on fundamental clinical implications because of the involvement of CSCs in cell migration, invasion, metastasis, and treatment resistance, which leads to the poor clinical outcome of cancer patients. Therefore, targeting CSCs will provide a novel therapeutic strategy for the treatment and/or prevention of tumors. However, the regulation of CSCs and its signaling pathways during tumorigenesis are not well understood. MicroRNAs (miRNAs) have been proved to act as key regulators of the post-transcriptional regulation of genes, which involve in a wide array of biological processes including tumorigenesis. The altered expressions of miRNAs are associated with poor clinical outcome of patients diagnosed with a variety of tumors. Therefore, emerging evidence strongly suggest that miRMAs play critical roles in tumor development and progression. Emerging evidence also suggest that miRNAs participate in the regulation of tumor cell growth, migration, invasion, angiogenesis, drug resistance, and metastasis. Moreover, miRNAs such as let-7, miR-21, miR-22, miR-34, miR-101, miR-146a, and miR-200 have been found to be associated with CSC phenotype and function mediated through targeting oncogenic signaling pathways. In this article, we will discuss the role of miRNAs in the regulation of CSC phenotype and function during tumor development and progression. We will also discuss the potential role of naturally occurring agents (nutraceuticals) as potent anti-tumor agents that are believed to function by targeting CSC-related miRNAs.
    Current drug targets 11/2012; · 3.93 Impact Factor
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    ABSTRACT: Garcinol, obtained from Garcinia indica, has exhibited some promising anticancer activity. In particular, our earlier work has demonstrated its ability to inhibit cell proliferation and induction of apoptosis in multiple cancer cell lines representative of breast, prostate, as well as pancreatic cancers. However, its exact mechanism of action remains largely unclear. Here we show that garcinol also targets signal transducer and activator of transcription-3 (STAT-3) signaling pathway. STAT-3 is frequently found to be activated in many cancer types and this is the first report on such action of garcinol leading to its anticancer effects. Garcinol inhibited total, as well as phosphorylated, STAT-3 in breast, prostate and pancreatic cancer cell lines and was also found to inhibit cell invasion of all the cancer cell lines tested. STAT-3 phosphorylation was inhibited by garcinol in a dose-dependent manner. We also observed an inhibitory effect of garcinol on IL-6-induced STAT-3 phosphorylation and production of urokinase-type plasminogen activator, vascular endothelial growth factor and matrix metalloproteinase-9, which might explain the reduced invasion and aggressiveness of cells treated with garcinol. The results were further verified in vivo using MDA-MB-231 breast cancer mouse xenograft model where administration of garcinol significantly inhibited tumor growth, and western blot analysis of remnant tumor lysates showed reduced STAT-3 expression and activation. These results suggest that garcinol may have translational potential as chemopreventive or therapeutic agent against multiple cancers and inhibition of STAT-3 signaling pathway is one of the mechanisms by which garcinol exerts its anticancer effects.
    Carcinogenesis 09/2012; · 5.27 Impact Factor
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    ABSTRACT: Tumor hypoxia with deregulated expression of hypoxia inducing factor (HIF) and its biological consequence leads to poor prognosis of patients diagnosed with solid tumors, resulting in higher mortality, suggesting that understanding of the molecular relationship of hypoxia with other cellular features of tumor aggressiveness would be invaluable for developing newer targeted therapy for solid tumors. Emerging evidence also suggest that hypoxia and HIF signaling pathways contributes to the acquisition of epithelial-to-mesenchymal transition (EMT), maintenance of cancer stem cell (CSC) functions, and also maintains the vicious cycle of inflammation, all of which contribute to radiation therapy and chemotherapy resistance. However, the detailed mechanisms by which hypoxia/HIF drive these events are not fully understood. Here, we have shown that hypoxia leads to increased expression of VEGF, IL-6, and CSC marker genes such as Nanog, Oct4 and EZH2, and also increased the expression of miR-21, an oncogenic miRNA, in prostate cancer (PCa) cells (PC-3 and LNCaP). The treatment of PCa cells with CDF, a novel Curcumin-derived synthetic analogue previously showed anti-tumor activity in vivo, inhibited the productions of VEGF and IL-6, and down-regulated the expression of Nanog, Oct4, EZH2 mRNAs, as well as miR-21 under hypoxic condition. Moreover, CDF treatment of PCa cells led to decreased cell migration under hypoxic condition. Taken together, these results suggest that the anti-tumor effect of CDF is in part mediated through deregulation of tumor hypoxic pathways, and thus CDF could become useful for cancer therapy.
    PLoS ONE 08/2012; 7(8):e43726. · 3.53 Impact Factor

Publication Stats

3k Citations
360.91 Total Impact Points

Institutions

  • 2003–2014
    • Karmanos Cancer Institute
      • Division of Hematology and Oncology
      Detroit, Michigan, United States
  • 2005–2013
    • Wayne State University
      • • Department of Pathology
      • • Department of Internal Medicine
      • • Division of Hematology and Oncology
      Detroit, Michigan, United States