Department of Stem Cell Biology and Regenerative Medicine Papers & Presentations Copyright (c) 2013 Thomas Jefferson University All rights reserved. http://jdc.jefferson.edu/stem_regenerativefp Recent documents in Department of Stem Cell Biology and Regenerative Medicine Papers & Presentations en-us Fri, 22 Feb 2013 17:40:12 PST 3600 Pressure-overload-induced subcellular relocalization/oxidation of soluble guanylyl cyclase in the heart modulates enzyme stimulation. http://jdc.jefferson.edu/stem_regenerativefp/4 http://jdc.jefferson.edu/stem_regenerativefp/4 Tue, 31 Jul 2012 13:30:29 PDT RATIONALE: Soluble guanylyl cyclase (sGC) generates cyclic guanosine monophophate (cGMP) upon activation by nitric oxide (NO). Cardiac NO-sGC-cGMP signaling blunts cardiac stress responses, including pressure-overload-induced hypertrophy. The latter itself depresses signaling through this pathway by reducing NO generation and enhancing cGMP hydrolysis.

OBJECTIVE: We tested the hypothesis that the sGC response to NO also declines with pressure-overload stress and assessed the role of heme-oxidation and altered intracellular compartmentation of sGC as potential mechanisms.

METHODS AND RESULTS: C57BL/6 mice subjected to transverse aortic constriction (TAC) developed cardiac hypertrophy and dysfunction. NO-stimulated sGC activity was markedly depressed, whereas NO- and heme-independent sGC activation by BAY 60-2770 was preserved. Total sGCα(1) and β(1) expression were unchanged by TAC; however, sGCβ(1) subunits shifted out of caveolin-enriched microdomains. NO-stimulated sGC activity was 2- to 3-fold greater in Cav3-containing lipid raft versus nonlipid raft domains in control and 6-fold greater after TAC. In contrast, BAY 60-2770 responses were >10 fold higher in non-Cav3 domains with and without TAC, declining about 60% after TAC within each compartment. Mice genetically lacking Cav3 had reduced NO- and BAY-stimulated sGC activity in microdomains containing Cav3 for controls but no change within non-Cav3-enriched domains.

CONCLUSIONS: Pressure overload depresses NO/heme-dependent sGC activation in the heart, consistent with enhanced oxidation. The data reveal a novel additional mechanism for reduced NO-coupled sGC activity related to dynamic shifts in membrane microdomain localization, with Cav3-microdomains protecting sGC from heme-oxidation and facilitating NO responsiveness. Translocation of sGC out of this domain favors sGC oxidation and contributes to depressed NO-stimulated sGC activity.

]]> Emily J Tsai et al. Animals Benzoic Acids Cardiomegaly Caveolin 3 Cyclic GMP Disease Models, Animal Down-Regulation Enzyme Activation Enzyme Activators Guanylate Cyclase Heme Hydrocarbons, Fluorinated Hydrolysis Membrane Microdomains Mice Mice, Inbred C57BL Mice, Knockout Myocytes, Cardiac Nitric Oxide Oxidation-Reduction Protein Transport Receptors, Cytoplasmic and Nuclear Signal Transduction Understanding the Warburg effect and the prognostic value of stromal caveolin-1 as a marker of a lethal tumor microenvironment. http://jdc.jefferson.edu/stem_regenerativefp/3 http://jdc.jefferson.edu/stem_regenerativefp/3 Thu, 23 Feb 2012 11:13:59 PST Cancer cells show a broad spectrum of bioenergetic states, with some cells using aerobic glycolysis while others rely on oxidative phosphorylation as their main source of energy. In addition, there is mounting evidence that metabolic coupling occurs in aggressive tumors, between epithelial cancer cells and the stromal compartment, and between well-oxygenated and hypoxic compartments. We recently showed that oxidative stress in the tumor stroma, due to aerobic glycolysis and mitochondrial dysfunction, is important for cancer cell mutagenesis and tumor progression. More specifically , increased autophagy/mitophagy in the tumor stroma drives a form of parasitic epithelial-stromal metabolic coupling. These findings explain why it is effective to treat tumors with either inducers or inhibitors of autophagy, as both would disrupt this energetic coupling. We also discuss evidence that glutamine addiction in cancer cells produces ammonia via oxidative mitochondrial metabolism. Ammonia production in cancer cells, in turn, could then help maintain autophagy in the tumor stromal compartment. In this vicious cycle, the initial glutamine provided to cancer cells would be produced by autophagy in the tumor stroma. Thus, we believe that parasitic epithelial-stromal metabolic coupling has important implications for cancer diagnosis and therapy, for example, in designing novel metabolic imaging techniques and establishing new targeted therapies. In direct support of this notion, we identified a loss of stromal caveolin-1 as a marker of oxidative stress, hypoxia, and autophagy in the tumor microenvironment, explaining its powerful predictive value. Loss of stromal caveolin-1 in breast cancers is associated with early tumor recurrence, metastasis, and drug resistance, leading to poor clinical outcome.

]]> Federica Sotgia et al. Mitochondrial oxidative stress drives tumor progression and metastasis: should we use antioxidants as a key component of cancer treatment and prevention? http://jdc.jefferson.edu/stem_regenerativefp/2 http://jdc.jefferson.edu/stem_regenerativefp/2 Thu, 23 Feb 2012 10:56:47 PST The functional role of oxidative stress in cancer pathogenesis has long been a hotly debated topic. A study published this month in BMC Cancer by Goh et al., directly addresses this issue by using a molecular genetic approach, via an established mouse animal model of human breast cancer. More specifically, alleviation of mitochondrial oxidative stress, via transgenic over-expression of catalase (an anti-oxidant enzyme) targeted to mitochondria, was sufficient to lower tumor grade (from high-to-low) and to dramatically reduce metastatic tumor burden by >12-fold. Here, we discuss these new findings and place them in the context of several other recent studies showing that oxidative stress directly contributes to tumor progression and metastasis. These results have important clinical and translational significance, as most current chemo-therapeutic agents and radiation therapy increase oxidative stress, and, therefore, could help drive tumor recurrence and metastasis. Similarly, chemo- and radiation-therapy both increase the risk for developing a secondary malignancy, such as leukemia and/or lymphoma. To effectively reduce mitochondrial oxidative stress, medical oncologists should now re-consider the use of powerful anti-oxidants as a key component of patient therapy and cancer prevention. Please see related research article: http://www.biomedcentral.com/1471-2407/11/191.

]]> Federica Sotgia et al. Animals Antineoplastic Agents Antioxidants Breast Neoplasms Catalase Disease Models, Animal Female Gene Expression Humans Mice Mitochondria Neoplasm Metastasis Neoplasms Oxidative Stress Protein Transport Rodent Diseases CAV1 inhibits metastatic potential in melanomas through suppression of the Integrin/Src/FAK signaling pathway. http://jdc.jefferson.edu/stem_regenerativefp/1 http://jdc.jefferson.edu/stem_regenerativefp/1 Wed, 15 Sep 2010 11:57:51 PDT Caveolin-1 (CAV1) is the main structural component of Caveolae which are plasma membrane invaginations that participate in vesicular trafficking and signal transduction events. Although, evidence has recently accumulated describing the function of CAV1 in several cancer types, its role in melanoma tumor formation and progression remains poorly explored. Here, by employing B16F10 melanoma cells as an experimental system, we directly explore the function of CAV1 in melanoma tumor growth and metastasis. We first show that CAV1 expression promotes proliferation while it suppresses migration and invasion of B16F10 cells in vitro. When orthotopically implanted in the skin of mice, B16F10 cells expressing CAV1 form tumors that are similar in size to their control counterpart. An experimental metastasis assay demonstrates that CAV1 expression suppresses the ability of B16F10 cells to form lung metastases in C57Bl/6 syngeneic mice. Additionally, CAV1 protein and mRNA levels are found to be significantly reduced in human metastatic melanoma cell lines and human tissue from metastatic lesions. Finally, we demonstrate that following integrin activation, B16F10 cells expressing CAV1 display reduced expression levels and activity of FAK and Src proteins. CAV1 expression also markedly reduces the expression levels of beta3 Integrin in B16F10 melanoma cells. In summary, our findings provide experimental evidence that CAV1 may function as an antimetastatic gene in malignant melanoma.

]]> Casey Trimmer et al.