Luis A. Espinoza

National Cancer Institute

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Mark E. Smulson

Georgetown University

J. Milburn Jessup

Institute for Bioscience and Biotechnology Research

Abid R. Mattoo

Virginia Cancer Institute

A. Hamid Boulares

Louisiana State University Health Sciences Center New Orleans

Luciana B. Crotti

Uniformed Services University of the Health Sciences

Snorri S. Thorgeirsson

National Cancer Institute

Cacilda Casartelli

Universidade de São Paulo

Jingyu Zhang

Second Affiliated Hospital of Nanchang University

Suhua Han

MedStar Georgetown University Hospital

J AGUILAR

Cooperative Institutions

National Cancer Institute

Georgetown University

National Institutes of Health

Center for Cancer Research

Georgetown University Medical Center

Universidade de São Paulo

Universidade do Estado do Rio de Janeiro

Universidade de Ribeirão Preto

Frederick National Laboratory for Cancer Research

Universidad Nacional de Colombia

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Abstract 339: Inhibition of NANOG/NANOGP8 downregulates MCL-1 in colorectal cancer (CRC) cells, enhances the efficacy of BH3 mimetics and inhibits clonogenicity

Cancer Research (2014)

Abid R. Mattoo Jingyu Zhang Luis A. Espinoza Snorri S. Thorgeirsson J. Milburn Jessup

Abstract Combining lentiviral (LV) delivered shRNA against NANOG (shNG-1) or NANOGP8 (shNp8-1) with BH3 mimetics (ABT-737 and ABT-199) was undertaken to determine whether inhibition of NANOG/NANOGP8 enhances the cytotoxic effect of these BH3 mimetics in Colorectal Cancer (CRC) cells. NANOG is a key transcription factor important for both pluripotency in embryonic stem cells and malignant transformation and progression of colorectal carcinoma (CRC). Inhibition of NANOG or its paralog NANOGP8 reduces the proliferation, stemness and tumorigenicity of CRC cells. The cytotoxic potential of ABT-737 or ABT-199, as single agents, was tested in the CRC cell lines- Clone A, CX-1 and LS174T that have high levels of anti-apoptotic BCL-2 family proteins. Treatment with ABT-737 or ABT-199 showed variable cytotoxicity in the three CRC lines with LS174T being the most resistant. Inhibition of NANOG and NANOGP8 with LVshNG-1 or LVshNp8-1 in these cell lines decreased expression of MCL-1. The combination of LVshNG-1 and/or LVshNp8-1, with ABT-737 produced enhanced killing of the CRC cells by caspase-dependent apoptosis. These results were were confirmed when LV shNG-1 or LV shNp8-1 was used in combination with ABT-199. siRNA targeting MCL-1 reproduced the effects of NANOG/NANOGP8 inhibition. The CRC cells that survived the combination treatment showed lower regrowth potential and reduced clonogenicity when re-plated in fresh media. These results demonstrate that inhibition of NANOGP8 or NANOG enhances the cytotoxicity of BH3 mimetics that target BCL-2 family members through inhibition of MCL-1 expression. Citation Format: Abid R. Mattoo, Jingyu Zhang, Luis A. Espinoza, Snorri S. Thorgeirsson, J. M. Jessup. Inhibition of NANOG/NANOGP8 downregulates MCL-1 in colorectal cancer (CRC) cells, enhances the efficacy of BH3 mimetics and inhibits clonogenicity. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 339. doi:10.1158/1538-7445.AM2014-339

Homeobox protein NANOG

Rex1

10.1158/1538-7445.am2014-339

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Autoimmune phenomena in human immunodeficiency virus infection

The American Journal of Medicine (1988)

J AGUILAR A BERMAN Luis A. Espinoza B BLITZ R LOCKEY

10.1016/0002-9343(88)90571-2

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Protection by antioxidants against toxicity and apoptosis induced by the sulphur mustard analog 2‐chloroethylethyl sulphide (CEES) in Jurkat T cells and normal human lymphocytes

British Journal of Pharmacology (2004)

Suhua Han Luis A. Espinoza Hongling Liao A. Hamid Boulares Mark E. Smulson

The author affiliations for the above paper were published incorrectly. The correct affiliations are shown above.

Jurkat cells

Sulfur mustard

10.1038/sj.bjp.0705802

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Enhanced TGFα-EGFR expression and P53 gene alterations contributes to gastric tumors aggressiveness

Cancer Letters (2004)

Luis A. Espinoza Luíz Gonzaga Tone José Barbieri Neto Roberto Silva Costa Qiming J. Wang

10.1016/j.canlet.2004.03.037

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Citations (14)

8 Role of Immunohistochemical Expression of Epidermal Growth Factor in Gastric Tumors

Handbook of immunohistochemistry and in situ hybridization of human carcinomas (2005)

Luis A. Espinoza

Expression (computer science)

10.1016/s1874-5784(05)80070-4

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Roles of Oxidative Stress and Glutathione Depletion in JP-8 Jet Fuel-Induced Apoptosis in Rat Lung Epithelial Cells

Toxicology and Applied Pharmacology (2002)

A. Hamid Boulares Francisco Contreras Luis A. Espinoza Mark E. Smulson

10.1006/taap.2002.9350

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Citations (33)

OCO-2's Delta II Rocket, First Stage

Luis A. Espinoza

Rocket (weapon)

Source

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The Involvement of Poly(ADP-ribosyl)ation in Defense against JP-8 Jet Fuel and Other Chemical Toxicants

CRC Press eBooks (2010)

Luis A. Espinoza Aria C. Attia Eric M. Brandon Mark E. Smulson

The covalent poly(ADP-ribosyl)ation of nuclear DNA-binding proteins in eukaryotic cells is a post-translational modification reaction related in part to the modulation of chromatin structure and function in DNA-damaged and apoptotic cells. This chapter presents evidence that constituents of Jet Propulsion Fuel-8 (JP-8) jet fuel may be genotoxic stressors that induce, in a dose-dependent manner, different levels of PARP-1 activation. Involvement of PARP-1 in the process of the inflammatory response, with the modulation of redox transcription factors and the production of pro-inflammatory factors, are discussed. The expression of genes whose products contribute to the cellular response to oxidative stress or chemical toxicants, including glutathione 5-transferases and cytochromes, was also prominently increased in lung tissue from rats exposed to JP-8 at the higher dose. This assay identified altered expression in stress response, or apoptosis-related genes to JP-8 in cultured lymphocytes.

Jet fuel

10.1201/9781420080216-11

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In vitrodifferentiation of rat liver derived stem cells results in sensitization to TNFα-mediated apoptosis

Hepatology (2004)

Aránzazu Sánchez Valentina M. Factor Luis A. Espinoza Insa S. Schroeder Snorri S. Thorgeirsson

Hepatic stem cells are activated after liver damage and have a critical role in tissue homeostasis and repair. Characterization of molecular and cellular events accompanying the expansion and differentiation of liver stem cells is essential for understanding the basic biology of stem cells and for facilitating clinical application of the stem cells. We assessed whether in vitro differentiation of putative hepatic progenitor (rat liver epithelial [RLE]) cells toward hepatocytic lineage affects the response to TNFα-mediated cytotoxicity, a common determinant of liver injury. The data show that 50% of differentiated cells underwent apoptosis after 6 hours of TNFα treatment whereas control RLE cells were resistant. Both cell types displayed mitochondrial depolarization and release of cytochrome c but the TNFα treatment resulted in activation of caspases 9 and 3 and the execution of apoptosis only in differentiated RLE cells. Apoptotic death was associated with increased ROS production and depletion of glutathione. Antioxidants completely prevented both glutathione depletion and apoptosis induced by TNFα in differentiated RLE cells. Conversely, glutathione-depleting agents sensitized control RLE cells to TNFα induced apoptosis. In conclusion , efficient antioxidant defense system involving glutathione renders hepatic progenitor cells resistant to TNFα-mediated apoptosis and acquisition of sensitivity to death stimuli is an implicit feature of the differentiation process. Supplementary material for this article can be found on the Hepatology website (http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html). (Hepatology 2004;40:590-599.)

10.1002/hep.20363

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Citations (26)

Prolonged poly(ADP-ribose) polymerase-1 activity regulates JP-8-induced sustained cytokine expression in alveolar macrophages

Free Radical Biology and Medicine (2007)

Luis A. Espinoza Mark E. Smulson Zhiguo Chen

Proinflammatory cytokine

Alveolar macrophage

PARP inhibitor

10.1016/j.freeradbiomed.2007.01.043

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Citations (19)