Amit Budhraja

Publications (18) View all

• Article: Epithelial-Mesenchymal Transition During Oncogenic Transformation Induced by Hexavalent Chromium Involves Reactive Oxygen Species-Dependent Mechanisms in Lung Epithelial Cells.

  Song-Ze Ding, Yuxiu Yang, Xiu-Ling Li, Audrey Michelli-Rivera, Shuangyin Han, Lei Wang, Poyil Pratheeshkumar, Xin Wang, Jian Lu, Yuanqin Yin, Amit Budhraja, Andrew J Hiltron
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  ABSTRACT: Hexavalent Chromium [Cr(VI)] is an important human carcinogen associated with pulmonary diseases and lung cancer. Exposure to Cr(VI) induces DNA damage, cell morphological change and malignant transformation in human lung epithelial cells. Despite extensive studies, the molecular mechanisms remain elusive, it is also not known if Cr(VI)-induced transformation might accompany with invasive properties to facilitate metastasis. We aimed to study Cr(VI)-induced epithelial-mesenchymal transition (EMT) and invasion during oncogenic transformation in lung epithelial cells. The results showed that Cr(VI) at low doses represses E-cadherin mRNA and protein expression, enhances mesenchymal marker vimentin expression and transforms the epithelial cell into fibroblastoid morphology. Cr(VI) also increases cell invasion and promotes colony formation. Further studies indicated that Cr(VI) uses multiple mechanisms to repress E-cadherin expression, including activation of E-cadherin repressors such as Slug, ZEB1, KLF8 and enhanced binding of HDAC1 in E-cadherin gene promoter, but DNA methylation is not responsible for the loss of E-cadherin. Catalase reduces Cr(VI)-induced E-cadherin and vimentin protein expression, attenuates cell invasion in matrigel and colony formation on soft agar. These results demonstrate that exposure to a common human carcinogen, Cr(VI), induces EMT and invasion during oncogenic transformation in lung epithelial cells and implicate in cancer metastasis and prevention.
  Toxicology and Applied Pharmacology 03/2013; · 4.45 Impact Factor
• Source

  Available from: Young-Ok Son

  Article: Ethanol enhances tumor angiogenesis in vitro induced by low-dose arsenic in colon cancer cells through hypoxia-inducible factor 1 alpha pathway.

  Lei Wang, Young-Ok Son, Songze Ding, Xin Wang, J Andrew Hitron, Amit Budhraja, Jeong-Chae Lee, Qinchen Lin, Pratheeshkumar Poyil, Zhuo Zhang, Jia Luo, Xianglin Shi
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  ABSTRACT: Health effects due to environmental exposure to arsenic are a major global health concern. Arsenic has been known to induce carcinogenesis and enhance tumor development via complex and unclear mechanism. Ethanol is also a well-established risk factor for many malignancies. However, little is known about the effects of co-exposure to arsenic and ethanol in tumor development. In this study, we investigate the signaling and angiogenic effect of co-exposure of arsenic and ethanol on different colon cancer cell lines. Results show that ethanol markedly enhanced arsenic-induced tumor angiogenesis in vitro. These responses are related to intracellular reactive oxygen species (ROS) generation, NAPDH oxidase activation, and up-regulation of PI3K/AKT and hypoxia-inducible factor 1 alpha (HIF-1α) signaling. We have also found that ethanol increase the arsenic-induced expression and secretion of angiogenic signaling molecules such as vascular endothelial growth factor (VEGF), which further confirmed the above observation. Antioxidant enzymes inhibited arsenic/ethanol-induced tumor angiogenesis, demonstrating that the responsive signaling pathways of co-exposure to arsenic and ethanol are related to ROS generation. We conclude that ethanol is able to enhance arsenic-induced tumor angiogenesis in colorectal cancer cells via the HIF-1α pathway. These results indicate that alcohol consumption should be taken into consideration in the investigation of arsenic-induced carcinogenesis in arsenic-exposed populations.
  Toxicological Sciences 08/2012; · 4.65 Impact Factor
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  Available from: Young-Ok Son

  Article: Cadmium induces carcinogenesis in BEAS-2B cells through ROS-dependent activation of PI3K/AKT/GSK-3β/β-catenin signaling.

  Young-Ok Son, Lei Wang, Pratheeshkumar Poyil, Amit Budhraja, J Andrew Hitron, Zhuo Zhang, Jeong-Chae Lee, Xianglin Shi
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  ABSTRACT: Cadmium has been widely used in industry and is known to be carcinogenic to humans. Although it is widely accepted that chronic exposure to cadmium increases the incidence of cancer, the mechanisms underlying cadmium-induced carcinogenesis are unclear. The main aim of this study was to investigate the role of reactive oxygen species (ROS) in cadmium-induced carcinogenesis and the signal transduction pathways involved. Chronic exposure of human bronchial epithelial BEAS-2B cells to cadmium induced cell transformation, as evidenced by anchorage-independent growth in soft agar and clonogenic assays. Chronic cadmium treatment also increased the potential of these cells to invade and migrate. Injection of cadmium-stimulated cells into nude mice resulted in the formation of tumors. In contrast, the cadmium-mediated increases in colony formation, cell invasion and migration were prevented by transfection with catalase, superoxide dismutase-1 (SOD1), or SOD2. In particular, chronic cadmium exposure led to activation of signaling cascades involving PI3K, AKT, GSK-3β, and β-catenin and transfection with each of the above antioxidant enzymes markedly inhibited cadmium-mediated activation of these signaling proteins. Inhibitors specific for AKT or β-catenin almost completely suppressed the cadmium-mediated increase in total and active β-catenin proteins and colony formation. Moreover, there was a marked induction of AKT, GSK-3β, β-catenin, and carcinogenic markers in tumor tissues formed in mice after injection with cadmium-stimulated cells. Collectively, our findings suggest a direct involvement of ROS in cadmium-induced carcinogenesis and implicate a role of AKT/GSK-3β/β-catenin signaling in this process.
  Toxicology and Applied Pharmacology 08/2012; 264(2):153-60. · 4.45 Impact Factor
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  Available from: Young-Ok Son

  Article: Cancer Prevention with Promising Natural Products: Mechanisms of Action and Molecular Targets.

  Poyil Pratheeshkumar, Chakkenchath Sreekala, Zhuo Zhang, Amit Budhraja, Songze Ding, Young-Ok Son, Xin Wang, Andrew Hitron, Kim Hyun-Jung, Lei Wang, Jeong-Chae Lee, Xianglin Shi
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  ABSTRACT: Cancer is the second leading cause of death worldwide. There is greater need for more effective and less toxic therapeutic and preventive strategies. Natural products are becoming an important research area for novel and bioactive molecules for drug discovery. Phytochemicals and dietary compounds have been used for the treatment of cancer throughout history due to their safety, low toxicity, and general availability. Many active phytochemicals are in human clinical trials. Studies have indicated that daily consumption of dietary phytochemicals have cancer protective effects against carcinogens. They can inhibit, delay, or reverse carcinogenesis by inducing detoxifying and antioxidant enzymes systems, regulating inflammatory and proliferative signaling pathways, and inducing cell cycle arrest and apoptosis. Epidemiological studies have also revealed that high dietary intakes of fruits and vegetables reduce the risk of cancer. This review discusses potential natural cancer preventive compounds, their molecular targets, and their mechanisms of actions.
  Anti-cancer agents in medicinal chemistry 05/2012;
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  Available from: Young-Ok Son

  Article: Quercetin Inhibits Angiogenesis Mediated Human Prostate Tumor Growth by Targeting VEGFR- 2 Regulated AKT/mTOR/P70S6K Signaling Pathways.

  Poyil Pratheeshkumar, Amit Budhraja, Young-Ok Son, Xin Wang, Zhuo Zhang, Songze Ding, Lei Wang, Andrew Hitron, Jeong-Chae Lee, Mei Xu, Gang Chen, Jia Luo, Xianglin Shi
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  ABSTRACT: Angiogenesis is a crucial step in the growth and metastasis of cancers, since it enables the growing tumor to receive oxygen and nutrients. Cancer prevention using natural products has become an integral part of cancer control. We studied the antiangiogenic activity of quercetin using ex vivo, in vivo and in vitro models. Rat aortic ring assay showed that quercetin at non-toxic concentrations significantly inhibited microvessel sprouting and exhibited a significant inhibition in the proliferation, migration, invasion and tube formation of endothelial cells, which are key events in the process of angiogenesis. Most importantly, quercetin treatment inhibited ex vivo angiogenesis as revealed by chicken egg chorioallantoic membrane assay (CAM) and matrigel plug assay. Western blot analysis showed that quercetin suppressed VEGF induced phosphorylation of VEGF receptor 2 and their downstream protein kinases AKT, mTOR, and ribosomal protein S6 kinase in HUVECs. Quercetin (20 mg/kg/d) significantly reduced the volume and the weight of solid tumors in prostate xenograft mouse model, indicating that quercetin inhibited tumorigenesis by targeting angiogenesis. Furthermore, quercetin reduced the cell viability and induced apoptosis in prostate cancer cells, which were correlated with the downregulation of AKT, mTOR and P70S6K expressions. Collectively the findings in the present study suggest that quercetin inhibits tumor growth and angiogenesis by targeting VEGF-R2 regulated AKT/mTOR/P70S6K signaling pathway, and could be used as a potential drug candidate for cancer therapy.
  PLoS ONE 01/2012; 7(10):e47516. · 4.09 Impact Factor