Christopher S. Gondi

University of Illinois Chicago

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Jasti S. Rao

Illinois College

110

Meena Gujrati

University of Illinois Urbana-Champaign

Dzung H. Dinh

University of Illinois Urbana-Champaign

Sajani S. Lakka

University of Illinois Chicago

Bharathi Gorantla

Illinois College

William C. Olivero

University of Illinois Urbana-Champaign

Jeffrey D. Klopfenstein

Illinois College

Chandramu Chetty

University of Wisconsin–Madison

Krishna Kumar Veeravalli

Illinois College

Praveen Bhoopathi

Virginia Commonwealth University

Cooperative Institutions

Illinois College

University of Illinois Urbana-Champaign

University of Illinois Chicago

Peoria campus of the University of Illinois System

The University of Texas MD Anderson Cancer Center

OSF Saint Francis Medical Center

Neurological Surgery

Moffitt Cancer Center

Universidade de Santiago de Compostela

Instituto de Investigación Sanitaria de Santiago

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Abstract 592: Downregulation of uPAR and uPA retards angiogenesis and proliferation and activates the extrinsic apoptotic pathway in pancreatic cancer cells

Cancer Research (2010)

Bharathi Gorantla Jasti S. Rao Jitendra Patel Christopher S. Gondi

Abstract Pancreatic cancer is one of the major causes of mortality in the United States. Despite well established chemotherapy and surgical resection strategies, the five-year mean survival rate is less than five percent. The activation of the uPAR/uPA system is an early event in the development of pancreatic ductal adenocarcinoma (PDAC), and uPAR gene amplification identifies a subgroup of particularly aggressive tumors. In the present study, we used two pancreatic cancer cell lines [MIA PaCa-2 (CRL1420) and PANC-1 (CRL1469)] to demonstrate the effect of uPA and uPAR downregulation. From the results, we observed that RNAi-expressing plasmids efficiently downregulated the expression of uPAR and uPA both at the mRNA and protein levels. In vitro and in vivo angiogenic assays revealed a significant decrease in angiogenic potential of CRL1420 (in vitro 26±3% and in vivo 13±2%) and CRL1469 (in vitro 23±1% and in vivo 10±2%) cells that were downregulated for both uPA and uPAR. From the antibody array analysis, we observed that the simultaneous downregulation of uPAR and uPA subsequently caused the downregulation of angiogenin and the overexpression of RANTES. The MTT proliferation assay results demonstrated that the downregulation of uPAR alone caused a decrease in proliferation (CRL1420: 24±3%; CRL1469: 38±2%) and downregulation of uPA alone caused a lesser decrease in proliferation (CRL1420: 19±2%; CRL1469: 26±1%) whereas the simultaneous downregulation of both uPA and uPAR caused the most significant decrease in proliferation in both cell lines (CRL1420: 84±4%; CRL1469: 93±3%). Further, FACS analysis demonstrated that the simultaneous downregulation of uPAR and uPA caused the accumulation of cells in the sub-G0/1 phase in both CRL1420 and CRL1469 cells. In addition, western blot analysis revealed that downregulation of uPA and uPAR caused the activation of caspase 8 and induced the cleavage of PARP, which is indicative of apoptosis; these results were confirmed by TUNEL assay. In conclusion, our results clearly demonstrate that the targeting of the uPAR-uPA system has potential clinical relevance for the treatment of pancreatic cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 592.

10.1158/1538-7445.am10-592

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Abstract 5212: Irradiation-induced uPAR promotes stemness via Wnt/β-catenin signaling in medulloblastoma cells

Cancer Research (2012)

Swapna Asuthkar Christopher S. Gondi Arun Kumar Nalla Kiran Kumar Velpula Bharathi Gorantla

Abstract Urokinase plasminogen activator receptor (uPAR) is known to promote invasion, migration and metastasis in cancer cells. In this study, we show that ionizing radiation (IR) induced uPAR has a role in Wnt/β-catenin signaling and mediates induction of cancer stem cells (CSC)-like properties in medulloblastoma cell lines UW228 and D283. We observed that IR induced the expression of uPAR, CSC markers such as CD44 and Msi-1, and activates Wnt/β-catenin signaling molecules. Overexpression of uPAR after IR treatment led to the activation of Wnt signaling, which was demonstrated by an increase in nuclear translocation of β-catenin and β-catenin-Lef/Tcf-mediated transactivation, thereby promoting cancer stemness. Quercetin, a potent Wnt/β-catenin inhibitor suppressed uPAR and uPAR-mediated Wnt/β-catenin activation. Treatment with shRNA specific for uPAR (pU) suppressed the β-catenin-Tcf/Lef-mediated transactivation both in vitro and in vivo. Further, we show that uPAR is physically associated with the Wnt effector molecule β-catenin using immunocytochemistry and immunohistochemistry; these results were confirmed by immunoprecipitation analysis. Most interestingly, we demonstrate for the first time that the localization of uPAR in the nucleus is associated with transcription factors (TF) and their specific response elements. The association of uPAR with β-catenin-Tcf/Lef complex and various other TF involved in neurogenesis during embryonic development and cancer demonstrates the receptor's possible role at generating CSC-like properties in primitive neuroectodermal tumor (PNET) cells of medulloblastoma. Considering all of the data, we conclude that uPAR is a potent activator of stemness, and the targeting of uPAR in combination with radiation has significant therapeutic implications. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5212. doi:1538-7445.AM2012-5212

Beta-catenin

10.1158/1538-7445.am2012-5212

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Pathophysiology (2025)

Shalan Alaamri Abdulhalim S. Serafi Zahir Hussain Shouq K. Bafail Mohammed A. Bafail

One of the major causes of hypertension (HT) is the transition of normal weight (NW) status to overweight (OW) status and obesity in a population, which leads to cardiovascular disease (CVD) and other disorders. A variety of factors/variables are involved in the development of HT and OW-related hypertension (OHT). However, we planned to investigate the pathophysiological role of serum leptin (Lep), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), total cholesterol (TC) and serum testosterone (ST) in OHT in middle-aged men. We consulted three groups of middle-aged men (age: 51-60 years)-an HT group (n: 97, high normal weight (HNW), body mass index (BMI): 23-24.9 kg/m2); an OHT group (n: 97, high overweight (HOW), BMI: 28-29.9 kg/m2) and a normal control group (NC, n: 98, HNW)-to investigate the variations in and correlations of Lep, IL-6, TNF-α, ST, TC and other variables. Significant variations were obtained for the comparisons of TNF-α, Lep, ST and TC for the patient groups. OHT vs. NC showed a significant difference for ST. OHT vs. NC and OHT vs. HT had significant variations for IL-6. Significant changes were obtained for the serum levels of TNF-α, Lep, IL-6, ST and TC among groups. Significant and positive linear associations were obtained for TNF-α, Lep, TC and IL-6. Significant and negative linear associations were found for ST plotted against Lep, TNF-α and IL-6. The current report provides pathophysiological evidence of the interactive role of serum Lep, TNF-α, ST, TC and IL-6 in middle-aged men with HT and OHT. We suggest that the changes we noted in the present study would be helpful for further BMI-based studies in various subcategories of NW, OW and obese subjects with/without HT.

10.3390/pathophysiology32010007

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Abstract 3319: Cell cycle regulation of glioblastoma progression by cord blood stem cells is mediated by downregulation of cyclin D1

Cancer Research (2011)

Kiran Kumar Velpula Venkata Ramesh Dasari Andrew J. Tsung Christopher S. Gondi Jeffrey D. Klopfenstein

Abstract Normal progression of the cell cycle requires sequential expression of cyclins. Rapid induction of cyclin D1 and its associated binding with cyclin-dependent kinases, in the presence or absence of mitogenic signals, is considered a rate-limiting step during cell cycle progression through the G1 phase. In the present study, human umbilical cord blood stem cells (hUCBSC) co-cultured with glioblastoma cells (U251 and 5310) not only induced G0-G1 phase arrest, but also reduced the number of cells at the S and G2-M phases of the cell cycle. Western and FACS analyses of cell cycle regulatory proteins showed decreased expression levels upon treatment with hUCBSC. Co-localization experiments under in vivo conditions in nude mice brain xenografts with cyclin D1 and CD81 antibodies demonstrated decreased expression of cyclin D1 in the presence of hUCBSC. Treatment with hUCBSC decreased expression of the cyclin D1 and CDK4 complex as well as cyclin D1 and CDK6 complexes. However, there was no significant change in the CDK4 and CDK6 complex. Our results indicate that hUCBSC can attenuate uncontrolled cell cycle progression of glioma cells by downregulating the expression levels of cyclin D1 and its partner kinases CDK4 and CDK6 at the cell cycle level. Our data elucidate a model to regulate glioma cell cycle progression in which hUCBSC act to control cyclin D1 induction and its partner kinases, CDK4 and CDK6, by mediating cell cycle arrest via G0-G1 arrest. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3319. doi:10.1158/1538-7445.AM2011-3319

Cyclin-dependent kinase 6

Cyclin D

Cyclin E

Cyclin A

Cyclin A2

Cyclin D2

Cyclin D3

Cyclin B

10.1158/1538-7445.am2011-3319

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Expression of antisense uPAR and antisense uPA from a bicistronic adenoviral construct inhibits glioma cell invasion, tumor growth, and angiogenesis

Oncogene (2003)

Christopher S. Gondi Sajani S. Lakka Niranjan Yanamandra Siddique Khawar Dzung H. Dinh

10.1038/sj.onc.1206535

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Citations (96)

Supplementary Figure 2 from Urokinase Plasminogen Activator Receptor and/or Matrix Metalloproteinase-9 Inhibition Induces Apoptosis Signaling through Lipid Rafts in Glioblastoma Xenograft Cells

Chandramu Chetty Sajani S. Lakka Praveen Bhoopathi Christopher S. Gondi Krishna Kumar Veeravalli

Supplementary Figure 2 from Urokinase Plasminogen Activator Receptor and/or Matrix Metalloproteinase-9 Inhibition Induces Apoptosis Signaling through Lipid Rafts in Glioblastoma Xenograft Cells

Lipid raft

Matrix metalloproteinase 9

10.1158/1535-7163.22484508.v1

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Supplementary Figures S1-S4 from Epigenetic Upregulation of Urokinase Plasminogen Activator Promotes the Tropism of Mesenchymal Stem Cells for Tumor Cells

Sai Murali Krishna Pulukuri Bharathi Gorantla Venkata Ramesh Dasari Christopher S. Gondi Jasti S. Rao

<p>Supplementary Figures S1-S4.</p>

10.1158/1541-7786.22519006

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Abstract 3453: SPARC overexpression inhibits cell proliferation in neuroblastoma and is partly mediated by tumor suppressor protein PTEN and AKT

Cancer Research (2012)

Praveen Bhoopathi Bharathi Gorantla G. S. Sailaja Christopher S. Gondi Meena Gujrati

Abstract Secreted protein acidic and rich in cysteine (SPARC) is also known as BM-40 or Osteonectin a multi-functional protein modulating cell-cell and cell-matrix interactions. In cancer, SPARC is not only linked with a highly aggressive phenotype, but it also acts as a tumor suppressor. In the present study, we sought to characterize the function of SPARC and its role in sensitizing neuroblastoma cells to radio-therapy. SPARC overexpression in neuroblastoma cells inhibited cell proliferation in vitro. Additionally, SPARC overexpression significantly suppressed the activity of AKT and this suppression was accompanied by an increase in the tumor suppressor protein PTEN both in vitro and in vivo. Restoration of neuroblastoma cell radio-sensitivity was achieved by overexpression of SPARC in neuroblastoma cells in vitro and in vivo. To confirm the role of the AKT in proliferation inhibited by SPARC overexpression, we transfected neuroblastoma cells with a plasmid vector carrying myr-AKT. AKT overexpression reversed SPARC-mediated PTEN and increased proliferation of neuroblastoma cells in vitro. PTEN overexpression in parallel with SPARC siRNA resulted in decreased AKT phosphorylation and proliferation in vitro. Taken together, these results establish SPARC as an effector of AKT-PTEN-mediated inhibition of proliferation in neuroblastoma in vitro and in vivo. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3453. doi:1538-7445.AM2012-3453

10.1158/1538-7445.am2012-3453

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Abstract 1735: Cathepsin B knocked down in pancreatic cancer cell lines fail to establish tumor in nude mice and influences the differential expression of circular RNA

Molecular and Cellular Biology / Genetics (2019)

Manu Gnanamony Liang Ge Tulika Chatterjee Christopher S. Gondi

Most malignant tumors show increased transcriptional activation of cathepsin B. Over expression of cathepsin B has been associated with different malignancies and this has made it an attractive pharmacological target. Tumor progression can be defined in several steps with respect to proteases. The first step requires that surrounding tissue be cleared to create a pathway for growth by modification and degradation of the extracellular matrix and basement membrane. Cathepsin B is one of the cathepsins that has been directly linked to extracellular matrix degradation. The second is a proteolytic cascade where activation of matrix metalloproteinases and urokinase plasminogen activator (uPA), results in further tissue invasion, this activation is known to be mediated by Cathepsin B. The last is cleavage of E-cadherin at adherin junctions, detaching cells to enter circulation and migrate. Cathepsin B plays a central role in these processes.Methods: In this study, we used two pancreatic cancer cell lines PANC-1 and MIA PaCa-2 that show differential sensitivity to gemcitabine. We knocked down the expression of cathepsin B in both PANC-1 and MIA PaCa-2 cells using CrisperCas9. We determined the tumorogenic potential of these down regulated cells and determined changes in gemcitabine sensitivity. Further, we determined the global expression profiles of circular RNA to predict the post-transcriptional regulation of associated microRNAs associated with chemo-sensitivity.Results: From the tumorogenic studies, we observed that both PANC-1 and MIA PaCa-2 cells downregulated for Cathepsin B failed to develop tumors in nude mice subcutaneous tumor models. Further, from the gemcitabine sensitivity studies using the MTT assay we observed that Cathepsin B down regulation reduced IC50 in both PANC and MIA PaCa-2 by at least 25%. Global analysis of circular RNA expression showed that Cathepsin B downregulated PANC-1 cells showed a 4.2 fold increase in the expression of hsa_circRNA_081069 and a 3.8 fold decrease in the expression of hsa_circRNA_104169. In case of MIA PaCa-2 cells downregulated for Cathepsin B, we observed that hsa_circRNA_042488 was upregulated by 15.9 fold and hsa_circRNA_101692 was decreased by 20.5 fold.Conclusions: From our observations, we conclude that Cathepsin B expression is necessary for (1) tumor establishment and development; (2) gemcitabine resistance and (3) modulation of circular RNA expression that regulate oncogenic and metabolic pathways necessary for tumorigenesis.Citation Format: Manu Gnanamony, Liang Ge, Tulika Chatterjee, Christopher S. Gondi. Cathepsin B knocked down in pancreatic cancer cell lines fail to establish tumor in nude mice and influences the differential expression of circular RNA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1735.

Cathepsin S

Cathepsin E

10.1158/1538-7445.sabcs18-1735

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SPARC Overexpression Inhibits Cell Proliferation in Neuroblastoma and Is Partly Mediated by Tumor Suppressor Protein PTEN and AKT

PLoS ONE (2012)

Praveen Bhoopathi Bharathi Gorantla G. S. Sailaja Christopher S. Gondi Meena Gujrati

Secreted protein acidic and rich in cysteine (SPARC) is also known as BM-40 or Osteonectin, a multi-functional protein modulating cell–cell and cell–matrix interactions. In cancer, SPARC is not only linked with a highly aggressive phenotype, but it also acts as a tumor suppressor. In the present study, we sought to characterize the function of SPARC and its role in sensitizing neuroblastoma cells to radio-therapy. SPARC overexpression in neuroblastoma cells inhibited cell proliferation in vitro. Additionally, SPARC overexpression significantly suppressed the activity of AKT and this suppression was accompanied by an increase in the tumor suppressor protein PTEN both in vitro and in vivo. Restoration of neuroblastoma cell radio-sensitivity was achieved by overexpression of SPARC in neuroblastoma cells in vitro and in vivo. To confirm the role of the AKT in proliferation inhibited by SPARC overexpression, we transfected neuroblastoma cells with a plasmid vector carrying myr-AKT. Myr-AKT overexpression reversed SPARC-mediated PTEN and increased proliferation of neuroblastoma cells in vitro. PTEN overexpression in parallel with SPARC siRNA resulted in decreased AKT phosphorylation and proliferation in vitro. Taken together, these results establish SPARC as an effector of AKT-PTEN-mediated inhibition of proliferation in neuroblastoma in vitro and in vivo.

Osteonectin

10.1371/journal.pone.0036093

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Citations (24)