Medicine and Health Sciences Commons^™

Microrna-200c Modulates The Expression Of Muc4 And Muc16 By Directly Targeting Their Coding Sequences In Human Pancreatic Cancer., Prakash Radhakrishnan, Ashley M. Mohr, Paul M. Grandgenett, Maria M. Steele, Surinder K. Batra, Michael A. Hollingsworth

Journal Articles: Biochemistry & Molecular Biology

Transmembrane mucins, MUC4 and MUC16 are associated with tumor progression and metastatic potential in human pancreatic adenocarcinoma. We discovered that miR-200c interacts with specific sequences within the coding sequence of MUC4 and MUC16 mRNAs, and evaluated the regulatory nature of this association. Pancreatic cancer cell lines S2.028 and T3M-4 transfected with miR-200c showed a 4.18 and 8.50 fold down regulation of MUC4 mRNA, and 4.68 and 4.82 fold down regulation of MUC16 mRNA compared to mock-transfected cells, respectively. A significant reduction of glycoprotein expression was also observed. These results indicate that miR-200c overexpression regulates MUC4 and MUC16 mucins in pancreatic …

Emerging Trends For Radioimmunotherapy In Solid Tumors., Maneesh Jain, Suprit Gupta, Sukhwinder Kaur, Moorthy P. Ponnusamy, Surinder K. Batra

Journal Articles: Biochemistry & Molecular Biology

Due to its ability to target both known and occult lesions, radioimmunotherapy (RIT) is an attractive therapeutic modality for solid tumors. Poor tumor uptake and undesirable pharmacokinetics, however, have precluded the administration of radioimmunoconjugates at therapeutically relevant doses thereby limiting the clinical utility of RIT. In solid tumors, efficacy of RIT is further compromised by heterogeneities in blood flow, tumor stroma, expression of target antigens and radioresistance. As a result significant efforts have been invested toward developing strategies to overcome these impediments. Further, there is an emerging interest in exploiting short-range, high energy α-particle emitting radionuclides for the eradication of …

Conservation Of Structure And Mechanism By Trm5 Enzymes., Thomas Christian, Howard Gamper, Ya-Ming Hou

Department of Biochemistry and Molecular Biology Faculty Papers

Enzymes of the Trm5 family catalyze methyl transfer from S-adenosyl methionine (AdoMet) to the N¹ of G37 to synthesize m¹ G37-tRNA as a critical determinant to prevent ribosome frameshift errors. Trm5 is specific to eukaryotes and archaea, and it is unrelated in evolution from the bacterial counterpart TrmD, which is a leading anti-bacterial target. The successful targeting of TrmD requires detailed information on Trm5 to avoid cross-species inhibition. However, most information on Trm5 is derived from studies of the archaeal enzyme Methanococcus jannaschii (MjTrm5), whereas little information is available for eukaryotic enzymes. Here we use human Trm5 (Homo sapiens; HsTrm5) …

Regulation Of Cell Death By Transfer Rna., Ya-Ming Hou, Xiaolu Yang

Department of Biochemistry and Molecular Biology Faculty Papers

SIGNIFICANCE: Both transfer RNA (tRNA) and cytochrome c are essential molecules for the survival of cells. tRNA decodes mRNA codons into amino-acid-building blocks in protein in all organisms, whereas cytochrome c functions in the electron transport chain that powers ATP synthesis in mitochondrion-containing eukaryotes. Additionally, in vertebrates, cytochrome c that is released from mitochondria is a potent inducer of apoptosis, activating apoptotic proteins (caspases) in the cytoplasm to dismantle cells. A better understanding of both tRNA and cytochrome c is essential for an insight into the regulation of cell life and death.

RECENT ADVANCES: A recent study showed that the …

An Integrated Clinico-Metabolomic Model Improves Prediction Of Death In Sepsis., Raymond J. Langley, Ephraim L. Tsalik, Jennifer C. Van Velkinburgh, Seth W. Glickman, Brandon J. Rice, Chunping Wang, Bo Chen, Lawrence Carin, Arturo Suarez, Robert P. Mohney, Debra H. Freeman, Mu Wang, Jinsam You, Jacob Wulff, J Will Thompson, M Arthur Moseley, Stephanie Reisinger, Brian T. Edmonds, Brian Grinnell, David R. Nelson, Darrell L. Dinwiddie, Neil A. Miller, Carol J. Saunders, Sarah Soden, Angela J. Rogers, Lee Gazourian, Laura E. Fredenburgh, Anthony F. Massaro, Rebecca M. Baron, Augustine M K Choi, G Ralph Corey, Geoffrey S. Ginsburg, Charles B. Cairns, Ronny M. Otero, Vance G. Fowler, Emanuel P. Rivers, Christopher W. Woods, Stephen F. Kingsmore

Manuscripts, Articles, Book Chapters and Other Papers

Sepsis is a common cause of death, but outcomes in individual patients are difficult to predict. Elucidating the molecular processes that differ between sepsis patients who survive and those who die may permit more appropriate treatments to be deployed. We examined the clinical features and the plasma metabolome and proteome of patients with and without community-acquired sepsis, upon their arrival at hospital emergency departments and 24 hours later. The metabolomes and proteomes of patients at hospital admittance who would ultimately die differed markedly from those of patients who would survive. The different profiles of proteins and metabolites clustered into the …

The Tumor Suppressor Tere1 (Ubiad1) Prenyltransferase Regulates The Elevated Cholesterol Phenotype In Castration Resistant Prostate Cancer By Controlling A Program Of Ligand Dependent Sxr Target Genes., William J. Fredericks, Jorge Sepulveda, Priti Lai, John E. Tomaszewski, Ming-Fong Lin, Terry Mcgarvey, Frank J. Rauscher, S. Bruce Malkowicz

Journal Articles: Biochemistry & Molecular Biology

Castrate-Resistant Prostate Cancer (CRPC) is characterized by persistent androgen receptor-driven tumor growth in the apparent absence of systemic androgens. Current evidence suggests that CRPC cells can produce their own androgens from endogenous sterol precursors that act in an intracrine manner to stimulate tumor growth. The mechanisms by which CRPC cells become steroidogenic during tumor progression are not well defined. Herein we describe a novel link between the elevated cholesterol phenotype of CRPC and the TERE1 tumor suppressor protein, a prenyltransferase that synthesizes vitamin K-2, which is a potent endogenous ligand for the SXR nuclear hormone receptor. We show that 50% …

Impaired Expression Of Protein Phosphatase 2a Subunits Enhances Metastatic Potential Of Human Prostate Cancer Cells Through Activation Of Akt Pathway., P Pandey, Parthasarathy Seshacharyulu, Srustidhar Das, Satyanarayana Rachagani, Moorthy P. Ponnusamy, Y Yan, Sonny L. Johansson, K Datta, Ming-Fong Lin, Surinder K. Batra

Journal Articles: Biochemistry & Molecular Biology

BACKGROUND: Protein phosphatase 2A (PP2A) is a dephosphorylating enzyme, loss of which can contribute to prostate cancer (PCa) pathogenesis. The aim of this study was to analyse the transcriptional and translational expression patterns of individual subunits of the PP2A holoenzyme during PCa progression.

METHODS: Immunohistochemistry (IHC), western blot, and real-time PCR was performed on androgen-dependent (AD) and androgen-independent (AI) PCa cells, and benign and malignant prostate tissues for all the three PP2A (scaffold, regulatory, and catalytic) subunits. Mechanistic and functional studies were performed using various biochemical and cellular techniques.

RESULTS: Through immunohistochemical analysis we observed significantly reduced levels of PP2A-A …

Id4 Deficiency Attenuates Prostate Development And Promotes Pin-Like Lesions By Regulating Androgen Receptor Activity And Expression Of Nkx3.1 And Pten, Pankaj Sharma, Ashley Knowell, Swathi Chinaranagari, Shravan Komaragiri, Peri Nagappan, Divya Patel, Mathew C. Havrda, Jaideep Chaudhary

Dartmouth Scholarship

Background: Inhibitor of differentiation 4 (Id4), a member of the helix-loop-helix family of transcriptional regulators has emerged as a tumor suppressor in prostate cancer. Id4 is expressed in the normal prostate where its expression is also regulated by androgens. In this study we investigated the effect of loss of Id4 (Id4-/-) on adult prostate morphology. Methods: Histological analysis was performed on prostates from 6-8 weeks old Id4-/-, Id4+/- and Id4+/+ mice. Expression of Id1, Sox9, Myc, androgen receptor, Akt, p-Akt, Pten and Nkx3.1 was investigated by immunohistochemistry. Androgen receptor binding on NKX3.1 promoter was studied by chromatin immuno-precipitation. Id4 was …

Androgens Upregulate Cdc25c Protein By Inhibiting Its Proteasomal And Lysosomal Degradation Pathways., Yu-Wei Chou, Li Zhang, Sakthivel Muniyan, Humera Ahmad, Satyendra Kumar, Syed Mahfuzul Alam, Ming-Fong Lin

Journal Articles: Biochemistry & Molecular Biology

Cdc25C is a cell cycle protein of the dual specificity phosphatase family essential for activating the cdk1/Cyclin B1 complex in cells entering into mitosis. Since altered cell cycle is a hallmark of human cancers, we investigated androgen regulation of Cdc25C protein in human prostate cancer (PCa) cells, including androgen-sensitive (AS) LNCaP C-33 cells and androgen-independent (AI) LNCaP C-81 as well as PC-3 cells. In the regular culture condition containing fetal bovine serum (FBS), Cdc25C protein levels were similar in these PCa cells. In a steroid-reduced condition, Cdc25C protein was greatly decreased in AS C-33 cells but not AI C-81 or …

Marked Improvement Of Cytotoxic Effects Induced By Docetaxel On Highly Metastatic And Androgen-Independent Prostate Cancer Cells By Downregulating Macrophage Inhibitory Cytokine-1., M Mimeault, Sonny L. Johansson, Surinder K. Batra

Journal Articles: Biochemistry & Molecular Biology

BACKGROUND: Overexpression of macrophage inhibitory cytokine-1 (MIC-1) frequently occurs during the progression of prostate cancer (PC) to androgen-independent (AI) and metastatic disease states and is associated with a poor outcome of patients.

METHODS: The gain- and loss-of-function analyses of MIC-1 were performed to establish its implications for aggressive and chemoresistant phenotypes of metastatic and AI PC cells and the benefit of its downregulation for reversing docetaxel resistance.

RESULTS: The results have indicated that an enhanced level of secreted MIC-1 protein in PC3 cells is associated with their acquisition of epithelial-mesenchymal transition features and higher invasive capacity and docetaxel resistance. Importantly, …

Muc4 Overexpression Augments Cell Migration And Metastasis Through Egfr Family Proteins In Triple Negative Breast Cancer Cells., Partha Mukhopadhyay, Imayavaramban Lakshmanan, Moorthy P. Ponnusamy, Subhankar Chakraborty, Maneesh Jain, Priya Pai, Lynette M. Smith, Subodh M. Lele, Surinder K. Batra

Journal Articles: Biochemistry & Molecular Biology

INTRODUCTION: Current studies indicate that triple negative breast cancer (TNBC), an aggressive breast cancer subtype, is associated with poor prognosis and an early pattern of metastasis. Emerging evidence suggests that MUC4 mucin is associated with metastasis of various cancers, including breast cancer. However, the functional role of MUC4 remains unclear in breast cancers, especially in TNBCs.

METHOD: In the present study, we investigated the functional and mechanistic roles of MUC4 in potentiating pathogenic signals including EGFR family proteins to promote TNBC aggressiveness using in vitro and in vivo studies. Further, we studied the expression of MUC4 in invasive TNBC tissue …

Potentials Of Plasma Ngal And Mic-1 As Biomarker(S) In The Diagnosis Of Lethal Pancreatic Cancer., Sukhwinder Kaur, Subhankar Chakraborty, Michael J. Baine, Kavita Mallya, Lynette M. Smith, Aaron Sasson, Randall Brand, Sushovan Guha, Maneesh Jain, Uwe Wittel, Shailender K. Singh, Surinder K. Batra

Journal Articles: Biochemistry & Molecular Biology

Pancreatic cancer (PC) is lethal malignancy with very high mortality rate. Absence of sensitive and specific marker(s) is one of the major factors for poor prognosis of PC patients. In pilot studies using small set of patients, secreted acute phase proteins neutrophil gelatinase associated lipocalin (NGAL) and TGF-β family member macrophage inhibitory cytokine-1 (MIC-1) are proposed as most potential biomarkers specifically elevated in the blood of PC patients. However, their performance as diagnostic markers for PC, particularly in pre-treatment patients, remains unknown. In order to evaluate the diagnostic efficacy of NGAL and MIC-1, their levels were measured in plasma samples …

Hypoxia-Inducing Factors As Master Regulators Of Stemness Properties And Altered Metabolism Of Cancer- And Metastasis-Initiating Cells., Murielle Mimeault, Surinder K. Batra

Journal Articles: Biochemistry & Molecular Biology

Accumulating lines of experimental evidence have revealed that hypoxia-inducible factors, HIF-1α and HIF-2α, are key regulators of the adaptation of cancer- and metastasis-initiating cells and their differentiated progenies to oxygen and nutrient deprivation during cancer progression under normoxic and hypoxic conditions. Particularly, the sustained stimulation of epidermal growth factor receptor (EGFR), insulin-like growth factor-1 receptor (IGF-1R), stem cell factor (SCF) receptor KIT, transforming growth factor-β receptors (TGF-βRs) and Notch and their downstream signalling elements such as phosphatidylinositol 3'-kinase (PI3K)/Akt/molecular target of rapamycin (mTOR) may lead to an enhanced activity of HIFs. Moreover, the up-regulation of HIFs in cancer cells may …