Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.3.5.1 (succinate dehydrogenase)
 8,177 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recently, enzymes of the tricarboxylic acid (TCA) cycle have emerged as novel tumor suppressors. In particular, mutations in the nuclear-encoded subunits of succinate dehydrogenase (SDHB, SDHC, and SDHD) cause paragangliomas and pheochromocytomas. Although the mechanism(s) by which disruption of mitochondrial metabolism leads to neoplasia is largely unknown, increasing evidence points to an activation of pseudohypoxia. In this study, we have shown that silencing of SDHB using DNA-based small interfering RNA resulted in major impairments in cellular proliferation, respiration, and a corresponding shift to glycolysis. The levels of reactive oxygen species, however, were unchanged. As expected, hypoxia-inducible factor-1 alpha (HIF-1 alpha) and HIF-2alpha were up-regulated in chronically silenced cells, suggesting that a pseudohypoxic state was attained. In addition, the c-Jun amino-terminal kinase and p38 kinase stress signaling proteins were hyperphosphorylated in SDHB-silenced cells. Microarray analysis showed that >400 genes were influenced (6-fold or more up-regulation or down-regulation) by silencing of SDHB, confirming the importance of the TCA cycle in cellular metabolism. Examples of dysregulated genes included those involved in proliferation, adhesion, and the hypoxia pathway. Of interest, SDHB-silenced cells had a greater capacity to adhere to extracellular matrix components, including fibronectin and laminin, than control cells, thus suggesting a possible mechanism of tumor initiation. Although transient silencing of the HIF-1 alpha transcription factor in SDHB-silenced cells had little effect on the expression of a subset of up-regulated genes, it partially reversed the adhesion phenotype to fibronectin, pointing to a potentially important role for HIF-1 in this process.
 ...
PMID:Cells silenced for SDHB expression display characteristic features of the tumor phenotype. 1851 64

Mitochondrial processes play an important role in tumor initiation and progression. In this review, we focus on three critical processes by which mitochondrial function may contribute to cancer: through alterations in glucose metabolism, the production of reactive oxygen species (ROS) and compromise of intrinsic apoptotic function. Alterations in cancer glucose metabolism include the Warburg effect, leading to a shift in metabolism away from aerobic respiration toward glycolysis, even when sufficient oxygen is present to support respiration. Such alterations in cellular metabolism may favor tumor cell growth by increasing the availability of biosynthetic intermediates needed for cellular growth and proliferation. Mutations in specific metabolic enzymes, namely succinate dehydrogenase, fumarate hydratase and the isocitrate dehydrogenases, have been linked to human cancer. Mitochondrial ROS may contribute to cancer via DNA damage and the activation of aberrant signaling pathways. ROS-dependent stabilization of the transcription factor hypoxia-inducible factor (HIF) may be a particularly important event for tumorigenesis. Compromised function of intrinsic apoptosis removes an important cellular safeguard against cancer and has been implicated in tumorigenesis, tumor metastasis, and chemoresistance. Each of the major mitochondrial processes is linked. In this review, we outline the connections between them and address ways these mitochondrial pathways may be targeted for cancer therapy.
 ...
PMID:Mitochondria in cancer: at the crossroads of life and death. 2180 1

Succinate dehydrogenase subunit B and D (SDHB and SDHD) mutations represent the most frequent cause of hereditary pheochromocytoma and paraganglioma (PPGL). Although truncation of the succinate dehydrogenase complex is thought to be the disease causing mechanism in both disorders, SDHB and SDHD patients exihibit different phenotypes. These phenotypic differences are currently unexplained by molecular genetics. The aim of this study is to compare disease dynamics in these two conditions via a Markov chain model based on 4 clinically-defined steady states. Our model corroborates at the population level phenotypic observations in SDHB and SDHD carriers and suggests potential explanations associated with the probabilities of disease maintenance and regression. In SDHB-related syndrome, PPGL maintenance seems to be reduced compared to SDHD (p = 0.04 vs 0.95) due to higher probability of tumor cell regression in SDHB vs SDHD (p = 0.87 vs 0.00). However, when SDHB-tumors give rise to metastases, metastatic cells are able to thrive with decreased probability of regression compared with SDHD counterparts (p = 0.17 vs 0.89). By constrast, almost all SDHD patients develop PGL (mainly head and neck) that persist throughout their lifetime. However, compared to SDHB, maintenance of metastatic lesions seems to be less effective for SDHD (p = 0.83 vs 0.11). These findings align with data suggesting that SDHD-related PPGL require less genetic events for tumor initiation and maintenance compared to those related to SDHB, but fail to initiate biology that promotes metastatic spread and metastatic cell survival in host tissues. By contrast, the higher number of genetic abnormalities required for tumor initiation and maintenance in SDHB PPGL result in a lower penetrance of PGL, but when cells give rise to metastases they are assumed to be better adapted to sustain survival. These proposed differences in disease progression dynamics between SDHB and SDHD diseases provide new cues for future exploration of SDHx PPGL behavior, offering considerations for future specific therapeutic and prevention strategies.
 ...
PMID:Mathematical modeling of disease dynamics in SDHB- and SDHD-related paraganglioma: Further step in understanding hereditary tumor differences and future therapeutic strategies. 3010 70