Cross Appointment with Simmons Cancer Institute
Dr. Nie is an Associate Professor in the Department of Medical Microbiology, Immunology and Cell Biology at SIU School of Medicine and a member of the Simmons Cancer Institute. Dr. Nie is a member of the American Association of Cancer Research and American Association for the Advancement of Sciences. He serves as an academic editor in PLoS ONE and a member of editorial boards for Journal of Bioanalysis & Biomedicine and Journal of Carcinogenesis & Mutagenesis.
Ph.D. in Chemistry and Biochemistry (1997), University of South Carolina, Columbia, South Carolina, USA
1997-2000 Postdoctoral Research Associate in Cancer Biology, Wayne State University School of Medicine, Detroit, Michigan, USA
2000-2005 Assistant Professor (non-tenure track); Department of Radiation Oncology, Wayne State University School of Medicine, Detroit, Michigan, USA.
2005-2009 Assistant Professor (tenure track); Department of Medical Microbiology, Immunology and Cell Biology, Southern Illinois University School of Medicine and Simmons Cancer Institute, Springfield, Illinois, USA.
2009 – Associate Professor (Tenure); Department of Medical Microbiology, Immunology and Cell Biology, Southern Illinois University School of Medicine and Simmons Cancer Institute, Springfield, Illinois, USA.
Project 1. 15-Lipoxygenase-2 as a tumor suppressor
15-Lipoxygenase-2 (ALOX15B) is an arachidonic acid metabolizing enzyme that has been implicated as a functional tumor suppressor for prostate cancer. The expression and activity of 15-LOX-2 are frequently suppressed during carcinogenesis of prostate, lung, esophageal and sebaceous gland. Based on the observations that restoration of 15-LOX-2 expression in prostate cancer cells inhibited both DNA replication and tumor development, 15-LOX-2 has been proposed as a functional tumor suppressor for prostate cancer but the mechanisms for 15-LOX-2 tumor suppressing activities and inactivation of 15-LOX-2 in cancer cells remain unknown. My colleagues and I found that a gain in wild type(wt)-15-LOX-2 expression did not abrogate the tumorigenicity of PC-3 or DU145 cells in animal models, but the palpable tumors with wt-15-LOX-2 expression restored grew much slower and were kept dormant. The data suggest that wt-15-LOX-2 sustains dormancy of tumors while having no discernible effects on tumor formation. I also demonstrated that the expression of VEGF (VEGF-A) was significantly reduced in prostate cancer cells with 15-LOX-2 expression restored. Currently, we are categorizing the mutations/polymorphisms of 15-LOX-2 gene loci (ALOX15B) in prostate cancer cells, studying the mechanism by which wt-15-LOX-2 to suppress VEGF expression, and determining the functionality of 15-LOX-2 mutants as a tumor suppressor. We expect to gain a better understanding of the loss of 15-LOX-2 functionality as a tumor suppressor during prostate carcinogenesis, and the mechanism by which 15-LOX-2 keeps tumor suppressed
Project 2. Thromboxane regulation of tumor progression and metastasis
Thromboxane A2 (TXA2) is a prostanoid produced by thromboxane synthase utilizing prostaglandin H2, the arachidonate product of cyclooxygenases, as the substrate. TXA2 has potent biological activities in platelet aggregation and vessel constriction. It should be noted that thrombosis is a recurrent problem for cancer patients and is a significant cause of cancer death. My colleagues and I were among the first to report a systematic investigation regarding the expression, activities, and functions of thromboxane A2 synthase in cancer cells (American Journal of Pathology, 2004). We also report for the first time an extensive investigation of the TXA2 receptor (TP) in tumor cells (Cancer Research 2008). In this most recent study, we examined the expression of TPs in prostate cancer cells and its role in reorganization of cytoskeleton during cell migration. Currently we try to determine the role of TPs in cancer metastasis. We have generated several breast cancer cell lines with the receptor ablated by shRNA and with stable expression of GFP and luciferase. The new cell lines enable us to monitor the metastatic spread of breast cancer cells in vivo, as functions of thromboxane A2 receptor, via small animal imaging. We also evaluate the effects of TP antagonists on spontaneous and experimental metastasis. We expect to define the functions of TP in the reorganization of cytoskeleton and cell motility and to validate TP as a target of intervention to block cancer metastasis and reduce cancer mortality.
Project 3. Drug metabolism, multi-drug resistance, and drug-drug interaction
Multi-drug resistance and adverse drug-drug interactions are impediments in effective cancer chemotherapy. The induction of drug metabolizing enzymes (DMEs) and efflux transporters has been regarded as one of the major mechanisms of drug resistance. As a master transcription factor of DMEs and efflux transporters, pregnane X receptor (PXR) is hypothesized as a novel regulator of multi-drug resistance in cancers. The role of PXR in determining the efficacy of chemotherapy is underscored by its two capabilities. First, PXR can be activated by a variety of structurally diverse compounds including many clinically used drugs and herbal supplements. Second, PXR activation stimulates the expression of important DMEs and efflux transporters, which in turn exert significant impacts on the metabolism and disposition of chemotherapeutics within tumor tissues. We are among the first to demonstrate the expression of PXR in prostate cancer cells and its potential role in modulating tumor responses to chemotherapy (Cancer Research, 2007). Our findings were also described in the Research Highlight section of the same issue of Cancer Research. Currently we are studying the activation of hPXR by common therapeutics and herbal supplements used by cancer patients and the effects of hPXR activation on the efficacy of subsequent chemotherapy. We expect that the proposed research will provide insights into whether tumor PXR is a determinant of tumor responses toward chemotherapy, multi-drug resistance, and/or adverse drug-drug interaction in combination therapy or when alternative medicine is used.
Project 4. Stemness of cancer cells and resistance to chemo-and radio-therapy
This research program was initiated to determine the role of cancer stem cells in resistance to chemo- and radio-therapy as well as in tumorigenicity. Recently we discovered the expression of embryonic stem cell transcription factors, notably Nanog and Oct3/4, in some cancers. Our recent focus is to characterize these two transcription factors expressed in tumor cells, to determine their functionalities in the stemness, tumorigenicity, and resistance of cancer cells toward chemo- and radio-therapy, and to investigate the regulation of Nanog and Oct3/4 activities by cellular signaling pathways.
- Nie D, Genge BR, Wu LNY, Wuthier RE. Defect in Formation of Functional Matrix Vesicles by Growth Plate Chondrocytes in Avian Tibial Dyschondroplasia: Evidence of Defective Tissue Vascularization. J. Bone Miner. Res. 10: 1625 - 1634, 1995.
- Wu LNY, Ishikawa Y, Nie D, Genge BR, Wuthier RE. Retinoic acid stimulates matrix calcification and initiates type I collagen synthesis in primary cultures of avian growth plate chondrocytes. J. Cell. Biochem. 65: 209-230, 1997.
- Nie D, Ishikawa Y, Yoshimori T, Wuthier RE, Wu LNY. Retinoic acid treatment elevates matrix metalloproteinase-2 protein and mRNA levels in avian growth plate chondrocyte cultures. J. Cell. Biochem. 68: 90-99, 1998.
- Sauer GR, Nie D, Wu LNY, Wuthier, R. E. Induction and characterization of metallothionein in chicken epiphyseal growth plate cartilage chondrocytes. J. Cell. Biochem. 68:110-120, 1998.
- Nie D, Ishikawa, Y., Guo, Y., Wu, L. N.Y., Genge, B. R., Wuthier, Sauer, G. R. Inhibition of terminal differentiation and matrix calcification in cultured avian growth plate chondrocytes by Rous Sarcoma Virus transformation. J. Cell. Biochem. 69: 453-462, 1998.
- Nie D, Hillman GG, Geddes T, Tang K, Pierson C, Grignon DJ, Honn KV. Platelet-type 12-lipoxygenase in a human prostate carcinoma stimulates angiogenesis and tumor growth. Cancer Research 58: 4047 - 4051, 1998.
- Tang K, Finley RL, Nie D, Honn KV. Identification of 12-lipoxygenase interaction with cellular proteins by yeast two-hybrid screening. Biochemistry 39:3185-3191, 2000.
- Nie D, Lamberti M, Zacharek A, Li L, Szekeres K, Tang K, Chen Y, Honn K. V. Thromboxane A2 regulation of endothelial cell migration, angiogenesis, and tumor metastasis. Biochem Biophys Res Commun 267:245-251, 2000.
- Nie D, Tang K, Digio C, Honn KV. Eicosanoid regulation of angiogenesis: Role of endothelial arachidonate 12-lipoxygenase. Blood 95:2304-2311, 2000.
- Szeker K, Mohit T, Nie D, Honn KV. Eicosanoid 12(S)-HETE activates phosphatidylinositol 3-kinase. Biochem Biophys Res Commun 275:690-695, 2000.
- Timar J, Raso E, Dome B, Li L, Grignon D, Nie D, Honn KV, Hagmann W. Expression, subcellular localization and putative function of platelet-type 12- lipoxygenase in human prostate cancer cell lines of different metastatic potential. Int J Cancer 87: 37-43, 2000.
- Wu LN, Lu M, Genge BR, Guo GY, Nie D, Wuthier RE. Discovery of sonic hedgehog expression in postnatal growth plate chondrocytes: Differential regulation of Sonic and Indian hedgehog by retinoic acid. J Cell Biochem 87:173–187, 2002.
- Nie D, Nemeth J, Qiao Y, Li L, Tang K, Hillman GG, Cher ML, Grignon DJ, Honn KV. Increased Metastatic Potential by Overexpression of Arachidonate 12-Lipoxygenase in Human Prostate Cancer Cells. Clinical and Experimental Metastasis 20:657-663, 2003.
- Kandouz M, Nie D, Pidgeon GP, Krishnamoorthy S, Maddipati KR, Honn KV. Platelet-type 12-Lipoxygenase Activates NF-kappa B in prostate Cancer Cells. Prostaglandins and other Lipid Mediatiors 71:189-204, 2003.
- Nie D, Che M, Zacharek A, Qiao Y, Cai Y, Tang K, Lamberti M, Grignon D, Honn KV. Differential expression of thromboxane synthase in prostate cancer: Role in tumor cell motility. American Journal of Pathology 164:429-439, 2004.
- Nie D, Krishnamoorth S, Jin R, Tang K, Chen U, Qiao Y, Zacharek A, Guo Y, Milanini J, Pages G, Honn KV. Mechanisms regulating tumor angiogenesis by 12-lipoxygenase in prostate cancer cells. Journal of Biological Chemistry 281: 18601 – 18609, 2006.
- Nie D. Cyclooxygenases and lipoxygenases in prostate and breast cancer. Frontier in Bioscience 12: 1574-1585, 2007.
- Wang M-T, Honn KV, and Nie D. Cyclooxygenases, prostanoids, and tumor progression. Cancer and Metastasis Review 26: 525-534, 2007. (Corresponding author).
- Pidgeon GP, Lysaght J, Krishnamoorthy S, Reynolds JV, O’Byrne K, Nie D, Honn KN. Lipoxygenase metabolism: roles in tumor progression and survival. Cancer Metastasis Rev. 26: 503-524, 2007.
- Tang Y, Olefumi L, Wang M-T, Nie D. Role of Rho GTPases in Breast Cancer. Frontiers in Biosciences 13: 759-776, 2008. (Corresponding author).
- Chen Y, Tang Y, Wang M-T, Zeng S, Nie D. Human Pregnane X Receptor and Resistance to Chemotherapy in Prostate Cancer. Cancer Research 67: 10361-10367, 2007. (Corresponding author).
- Nie D, Guo Y, Yang D, Tang Y, Chen Y, Wang M-T, Zacharek A, Yang Q, Che M, Honn KV. Thromboxane A2 Receptors in Prostate Carcinoma: Expression and its Role in Regulating Cell Motility via Small GTPase Rho. Cancer Research 68: 115-121, 2008. (Corresponding author).
- Zhu S, Wu H, Wu F, Nie D, Sheng S. Mo YY. MicroRNA-21 targets tumor suppressor genes in invasion and metastasis. Cell Research 18: 350-359, 2008.
- Tang Y, Wang M-T, Chen Y, Che M, Honn KV, Johnson S, Akers G, and Nie D. Downregulation of Vascular Endothelial Growth Factor and Induction of Tumor Dormancy by 15-Lipoxygenase-2 in Human Prostate Cancer. International Journal of Cancer 124: 1545 – 1551, 2009.
- Chen Y, and Nie D. Pregnane X receptor and its potential role in drug resistance in cancer treatment. Recent Patents on Anti-Cancer Drug Discovery 4: 19-27, 2009.
- Chen Y, Tang Y, Chen S, and Nie D. Regulation of breast cancer cell responses to chemotherapy by pregnane X receptor. Cancer Biology & Therapy. 8: 1265 - 1272. 2009.
- Walia V, Ming D, Kumar S, Nie D, and Elble R. hCLCA2 is a p-53-inducible inhibitor of breast cancer cell proliferation. Cancer Research 69: 6624 – 6632, 2009.
- Tang Y, Chen Y, Jiang H, and Nie D. Promotion of tumor development in prostate cancer by progerin. Cancer Cell Int. 10: 47, 2010.
- Krishnamoorthy S, Jin R, Cai Y, Maddipati KR, Nie D, Pagès G, Tucker SC, Honn KV. 12-Lipoxygenase and the regulation of hypoxia-inducible factor in prostate cancer cells. Exp Cell Res 316(10): 1706-15, 2010.
- Chen Y, Tang Y, Robbins GT, and Nie D. Camptothecin attenuates cytochrome P450 3A4 induction by blocking the activation of human pregnane X receptor. J Pharmacol Exp Therapy 334(3): 999-1008, 2010.
- Tang Y, Jiang H, Chen Y, and Nie D. GPR43, a G protein coupled receptor for short chain fatty acids, is a functional tumor suppressor in the colon. International Journal of Cancer 128(4): 847-56, 2011. PMID: 20979106. Selected by Faculty of 1000 in June, 2011 (as top 2% of published articles in biology and medicine).
- Tang Y, Chen Y, Jiang H, and Nie D. The role of short-chain fatty acids in orchestrating two types of programmed cell death in colon cancer. Autophagy 7(2):235-7, 2011.
- Tang Y, Chen Y, Jiang H, and Nie D. Short-chain fatty acids induced autophagy serves as an adaptive strategy for retarding mitochondria-mediated apoptotic cell death. Cell Death Differ 18(4):602-18, 2011.
- Robbins GT, Nie D. PPAR gamma, bioactive lipids, and cancer progression. Front Biosci. 17:1816-34, 2012.
- Malik B, Nie D. Cancer stem cells and resistance to chemo and radio therapy. Front Biosci (Elite Ed) 4:2142-9, 2012.
- Chen Y, Tang Y, Guo C, Wang J, Boral D, Nie D. Nuclear receptors in the multidrug resistance through the regulation of drug-metabolizing enzymes and drug transporters. Biochem Pharmacol. 2012 Feb 4. [Epub ahead of print].