bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1117: Investigating the role of PTEN-induced kinase 1 in cancer development and pathogenesis
Authors: O'Flanagan Ciara H. , Morais Vanessa , Kloos Karina , Wurst Wolfgang , de Strooper Bart , O'Neill Cora 
Published: August 2012

Abstract
PTEN-induced kinase 1 (PINK1) was first identified in cancer cells as a gene up-regulated by overexpression of the central tumour suppressor, PTEN. Loss-of-function mutations in PINK1 were subsequently discovered to cause autosomal recessive Parkinson's disease (ARPD). While much research has focused on the proposed mechanism(s) through which loss of PINKI function causes neurodegeneration, some studies indicate a potential role for this serine/threonine kinase in cancer cell biology. PINK1 is known to be a pro-survival kinase, protecting cells from several stressors, and is a key controller of mitochondrial integrity, morphology and function. This study aimed to understand the function of PINK1 in the development of cancer. Using SV40 immortalised PINK1 -/- mouse embryonic fibroblasts (MEFs), we show that loss of PINK1 results in reduced cell proliferation and foci formation, as well as decreased invasiveness. Overexpression of human PINK1 in these cells rescues these phenotypes and increases migratory capacity, indicating a tumour promoting role for PINK1. Furthermore, PINK1 loss increases autophagy and levels of reactive oxygen species, as well as enhancing mitochondrial fission. Notably, we identify PINK1 as a novel controller of cell cycle progression events which are critical to tumourigenesis. These results indicate an important function for PINK1 in cancer cell development.
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 1117. doi:1538-7445.AM2012-1117
Abstract 1119: The oxidation of proline by proline oxidase provides a regulated source of ROS for mitochondria derived cellular signaling
Authors: Hancock Chad N. , Phang James 
Published: August 2012

Abstract
A role for reactive oxygen species (ROS) in intracellular signaling has been generally accepted, but the organellar localization, the enzymatic source and the regulation of ROS generation are not well understood. Recent work by others has focused on mitochondria as a source of ROS and specifically on the reduction of oxygen by electrons from complex III to form superoxide. The accessibility of complex III to the mitochondrial intermembrane space and cytosol provides an attractive hypothesis for mitochondrial ROS as regulators of cellular redox signaling. We now report that the regulated metabolism of proline makes it a special substrate for this process. Proline oxidase (POX) is an inner mitochondrial membrane protein that oxidizes proline to generate superoxide as well as ATP. Work in our laboratory has documented that POX activity is highly regulated during genotoxic and metabolic stress. Inducers of POX include p53, and proline-dependent ROS play a role in mitochondrial apoptosis. PPAR-γ and its ligands also induce POX but depending on the metabolic context, POX initiates autophagy as well as apoptosis. Mechanistic models for ROS generation by POX have come from microorganisms. PutA, the prokaryotic homolog of POX can generate ROS by electrons reducing oxygen directly from its catalytic center. On the other hand, in S. cerevisiae, the POX homolog, Put1, has been shown to directly interact with ubiquinone, thereby contributing electrons derived from proline oxidation into the electron transport chain. In this work, we now report that human POX interacts directly with ubiquinone and that POX activity is markedly increased by the presence of ubiquinone. In addition, by using selective inhibitors of electron transport, we demonstrate that electrons derived from proline can be converted to superoxide by complex III of the electron transport chain. These radicals are directed into both the mitochondrial matrix as well as into the intermembrane space and the cytosol. Thus, POX is not only specifically regulated but also specially located and coupled to the mitochondrial electron transport chain to mediate ROS signaling. These POX- mediated mechanisms provide important insights into its novel apoptotic and metabolic tumor suppressive functions.
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 1119. doi:1538-7445.AM2012-1119
Abstract 112: An endogenous mTOR inhibitor, PRAS40, is upregulated in lung cancer and contributes to tumor cell invasion and chemoresistance
Authors: Li Zenggang , Du Yuhong , Sica Gabriel , Ramalingam Suresh S , Gal Anthony A , Pan Lin , Tighiouart Mourad Mourad , Khuri Fadlo R. Fadlo R. , Fu Haian 
Published: August 2012

Abstract
The proline-rich Akt substrate of 40-kDa (PRAS40) has recently been identified as a regulatory component of, TORC1 (a complex composed of mTOR, GβL, DEPTOR, RAPTOR and PRAS40)Phosphorylation of Thr246 on PRAS40 by PKB/Akt, and Ser183 and Ser221 by mTOR results in the dissociation of PRAS40 from TORC1, and binding of PRAS40 to 14-3-3 proteins. Negative mTOR regulators usually play anti-tumorigenesis roles (like TSC1-TSC2, LKB1 and PTEN). Unexpectedly, PRAS40 has been shown to acted as a pro-tumorigenic factor in certain types of cancer cells. To better understand the role of PRAS40 in cancer, we have carried out a series of cell culture and patient tumor tissue based studies. Here, we report that PRAS40 was upregulated in most of the non-small cell lung cancer (NSCLC) cell lines examined when compared to normal lung epithelial cell lines. Further immonuhistochemistry (IHC) studies confirmed the overexpression of PRAS40 in tumor tissues from NSCLC patients. Significantly, nearly 60% of cancer tissues from NSCLC patients exhibited considerably higher levels of PRAS40 protein than those in paired normal lung tissue. Such high levels of PRAS40 expression appear to be required for tumor progression as silencing of PRAS40 by shRNA decreased the cell invasion ability of NSCLC cells. Subsequently, we investigated whether PRAS40 can influence the sensitivity of NSCLC cells to chemotharepitic drugs. Our data demonstrated that downregulation of PRAS40 protein increased the sensitivity of NSCLC cells to chemotherapeutic agents, such as etopside and perifosine. In summary, our results strongly support a pro-tumorigenic role for PRAS40 and suggest PRAS40 could be a potential NSCLC therapeutic target.
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 112. doi:1538-7445.AM2012-112
Abstract 1120: α-Tocopherol protects cells from lipid peroxidation and rescues tumorigenic phenotypes in CS/CSL patients with germline SDHx variants
Authors: Ni Ying , Eng Charis 
Published: August 2012

Abstract
Cowden syndrome (CS), a Mendelian autosomal-dominant disorder, predisposes to breast, thyroid, and other cancers. Germline mutations in phosphatase and tensin homolog (PTEN) have been found in 25% of classic CS individuals accrued from the community. Additionally, we have shown that germline variations in succinate dehydrogenase genes (SDHx) occur in 8% of 608 PTEN mutation-negative CS and CS-like (CSL) individuals (SDHvar+), compared to 0/700 controls (p&lt;0.0001, Fisher's 2-tailed exact test). SDHx genes encode for mitochondrial complex II which lies at the crossroads of electron transport and the tricarboxylic acid cycle. We previously showed that SDHx variants result in elevated reactive oxygen species (ROS) and in disruption of such mitochondrial metabolites as flavin adenine dinucleotide (FAD) and nicotinamide adenine dinucleotide (NAD) equilibrium in CS/CSL patient-derived lymphoblastoid cells. Consequently, improper NADH quinone oxidoreductase 1 (NQO1)-p53 interaction results in destabilization of p53 and apoptosis resistance. Here we further demonstrate that elevated ROS production results in higher lipid peroxidation in SDHvar+ cells compared to healthy control cells. This increased oxidative stress led to increased mutation accumulation in mitochondrial hypervariable region II (HVRII) in samples with SDHx variants compared to controls. Interestingly, α-tocopherol treatment, but not other antioxidants, can rescue SDHvar+ cells from apoptosis resistance. This lipid soluble vitamin E, functions as a peroxyl-radical scavenger, protecting SDHvar+ cells from oxidative damage. We observed down regulated lipid peroxidation in SDHvar+ cells after α-tocopherol exposure, as well as recovered p53 expression and FAD/NAD levels. We conclude that α-tocopherol selectively protects SDHvar+ cells from redox stress and downstream tumorigenic reprogramming, which may have intriguing clinical implications such as using vitamin E as a potential preventive adjunct for CS/CSL individuals with SDHx variants.
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 1120. doi:1538-7445.AM2012-1120
Abstract 1121: ER-negative breast cancer survive mitochondrial IMS-stress via SIRT3 activation
Authors: Papa Luena , Shimonovoch Shahar , Germain Doris 
Published: August 2012

Abstract
Mitochondrial dysfunction is central in carcinogenesis and has been associated with elevated levels of Reactive Oxygen Species (ROS). While moderate levels of ROS activate signaling cascade promoting tumor progression, high levels of ROS can lead to cell death. We previously demonstrated that Estrogen Receptor (ER)-positive breast cancer cells activate ER to overcome the mitochondrial impairment and reduce high levels of ROS induced by stress in the inter-mitochondrial membrane space (IMS). The ultimate outcome of ER activation is induction of a novel Unfolded Protein Response (UPR) that involves up-regulation of NRF-1, a major regulator of mitochondrial biogenesis as well as induction of OMI and proteasome, two critical elements of protein quality control required to monitor the quality of IMS proteins. In the present work, we have evidence that ER-negative breast cancer cells trigger a distinct mechanism to cope up with IMS-stress. Due to the lack of ER, the stress from the IMS is extended into the matrix of mitochondria leading to activation of the matrix deacetylase, SIRT3. SIRT3 is required to increase the antioxidant capacity by up-regulating the antioxidant enzyme, MnSOD and therefore reducing ROS. In addition, our results reveal that SIRT3 is essential for removal of the irreversible impaired mitochondria through mitophagy. Overall, our data indicate that ER-positive and ER-negative breast cancer induce different mechanism to conquer mitochondrial malfunction coupled with ROS overproduction and maintain their cellular integrity.
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 1121. doi:1538-7445.AM2012-1121
Abstract 1122: Lipoic acid analogs induce ROS, leading to potent mitochondrial enzyme inhibition, metabolic dysfunction and cell death in tumor cells
Authors: Stuart Shawn D. , Zachar Zuzana , Gupta Sunita , Rodriguez Robert , Shorr Robert , Bingham Paul M. 
Published: August 2012

Abstract
The targeting of tumor cell metabolism has emerged as an attractive candidate for chemotherapeutics. In particular, tumor cell mitochondria are dramatically reprogrammed to generate large amounts of biosynthetic intermediates to fuel cell division. We previously described a novel class of non-redox active lipoic acid analogs (“thioctoids”) which effect dramatic inactivation of the mitochondrial enzyme complex pyruvate dehydrogenase (PDH) (PMID:21769686). We have recently completed a comprehensive metabolomic study indicating that thioctoids down-regulate multiple mitochondria-associated enzymes. Each of these target enzymes are key control points for entry of carbon into the TCA cycle, including the alpha-ketoglutarate dehydrogenase complex and the branch-chain dehydrogenase/amino trasferase complex. In addition we will present data that reactive oxygen species (ROS) play a direct regulatory role in these inactivations and are a major contributor to the resultant cell cycle arrest and multiple cell death pathways which follow. Taken together, our results indicate that thioctoids are potent inhibitors of tumor cell mitochondrial energy metabolism, owing, apparently, to the central regulatory role of lipoic acid in mitochondrial lipoamide dehydrogenase-containing enzyme complexes. We hypothesize that thioctoids are ‘misread’ by these complexes resulting in increased levels of ROS leading to the further shutdown of redox-sensitive metabolic enzymes and ultimately cell death. As a consequence of these novel properties, thioctoids attack tumor-specific metabolism far more broadly and pervasively than other agents directed at individual metabolic steps or activities. Thioctoids are exceptionally well tolerated in animal studies and as a result may have high clinical potential. They are currently in early stage human clinical trials.
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 1122. doi:1538-7445.AM2012-1122
Abstract 1124: Increased oxidative stress and mitochondrial dysfunction in Zucker diabetic fatty rat tissues
Authors: Raza Haider , Howarth Frank C. , John Annie 
Published: August 2012

Abstract
The Zucker diabetic fatty (ZDF) rat is a genetic model in which the homozygous (FA/FA) animals develop obesity and type 2 diabetes. Oxidative stress and increased expression of inflammatory signals and cytokines are the hallmarks of type 2 diabetes and cancer. Insulin signaling and IGF receptors are also affected in cancer progression. The precise molecular mechanism of disease progression or protection/prevention is, however, not clear. We, therefore, have investigated molecular and metabolic targets affected in the liver, kidney, brain and pancreas of ZDF (30 weeks old) male rats. Our results have demonstrated that GSH-dependent redox metabolism and mitochondrial respiratory function are affected in ZDF rats when compared to Zucker lean (ZL) control rats (n=6 each). With the exception of brain, cytosolic GSH content in the tissues of ZDF rats was significantly lower than ZL rats. GSH-reductase activity and GSH-conjugation by glutathione S-transferase were also lower in ZDF rat tissues. Although there was no significant increase in the apocynin sensitive- NADPH oxidase -dependent reactive oxygen species (ROS) production in the liver, DCFDA-probed ROS production and reactive nitrogen species (RNS) production were significantly higher in ZDF rat tissues. Higher levels of lipid and protein peroxidation were also observed in ZDF rat tissues. Western blot analysis also confirmed increased expression of iNOS and COX-2 suggesting an increase in oxidative stress and inflammatory markers in ZDF rat tissues. Our results have demonstrated that the increased oxidative stress in ZDF rats was accompanied by lower activities of mitochondrial respiratory complexes and decreased ATP synthesis. Taken together, our results show that ZDF rats are prone to develop complications associated with oxidative stress, inflammation and mitochondrial dysfunction as seen in the pathogenesis of cancer and diabetes. These results might have implications in designing strategies for cancer and diabetes prevention. (Supported by the Terry Fox Cancer Research Fund and a fund from FMHS Research Committee).
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 1124. doi:1538-7445.AM2012-1124
Abstract 1125: Consumption of oxygen: a mitochondrial-generated progression signal of advanced cancer
Authors: Cook Cody C. , Kim Ara , Terao Shuji , Gotoh Akinobu , Higuchi Masahiro 
Published: August 2012

Abstract
The majority of mortality from prostate cancer occurs when the disease progresses to a highly malignant phenotype. Changes in the mitochondrial genome such as mutation, deletion and depletion are common in cancer and can determine advanced phenotype of cancer; however, detailed mechanisms have not been elucidated. We observed that loss of the mitochondrial genome reversibly induced overexpression and activation of proto-oncogenic Ras, especially KRas-4A, responsible for the activation of AKT and ERK leading to advanced phenotype of prostate and breast cancer. Maturation of Ras, possibly prenylation of Ras, was required for Ras activation and was induced by the overexpression of 3- hydroxy-3-methyl-glutaryl-CoA reductase (HMGR), the rate-limiting enzyme of the mevalonate pathway. Hypoxia is known to cause accumulation of intermediate sterols which induces proteasomal degradation of HMGR. Well-differentiated and less aggressive prostate and breast cancer cells with high mitochondrial DNA (mtDNA) content consumed a large amount of oxygen and induced intracellular hypoxia. Loss of mitochondrial genome content reduced oxygen consumption and an increase in oxygen concentration (hypoxic-to-normoxic shift) in the cells. Inhibition of oxygen consumption by the reduction of mitochondrial genome content induced overexpression of HMGR through hypoxic-to-normoxic shift. Subsequently, the endogenous induction of the mevalonate pathway activated Ras that mediates advanced phenotype. Reconstitution of the mitochondrial genome or external hypoxic condition, to reverse the hypoxic-to-normoxic shift, diminished the endogenous induction of the mevalonate pathway and the activation of proto-oncogenic Ras. Reduction of mitochondrial genome content was associated with aggressive phenotype of prostate cancer in vitro cell line model and tissue specimens from prostate cancer patients in vivo. Our results elucidate a coherent mechanism that directly links the changes in mitochondrial genome with the advanced progression of the disease.
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 1125. doi:1538-7445.AM2012-1125
Abstract 1126: Mitochondrial DNA copy number and colorectal cancer risk: Results from the Shanghai Women's Health Study
Authors: Huang Bo , Gao Yu-Tang , Shu Xiao Ou , Wen Wanqing , Yang Gong , Li Guoliang , Ji Bu-Tian , Li Hong-Lan , Chow Wong-Ho , Zheng Wei , Cai Qiuyin 
Published: August 2012

Abstract
Mitochondria play an important role in cellular energy metabolism, free radical generation, and apoptosis. Cumulative evidence suggests that mtDNA copy number may be a biomarker for cancer risk. Using a nested case-control design, we evaluated mtDNA copy number in peripheral blood cells in relation to colorectal cancer risk. Included in the study were 436 colorectal cancer cases and 881 matched controls identified from the Shanghai Woman's Health Study, a population-based, prospective cohort study conducted among Chinese women. Relative mtDNA copy number was determined in triplicate by a quantitative real-time PCR assay using peripheral blood cell DNA samples collected at the time of study enrollment, prior to cancer diagnosis. Baseline levels of mtDNA copy number were lower among women who subsequently developed colorectal cancer (geometric mean = 0.271, 95% CI: 0.263-0.279) than those who remained cancer-free (geometric mean = 0.281, 95% CI: 0.275-0.288) (P=0.0274). Multivariate adjusted odds ratios were 1.15 (95% CI: 0.80-1.65), 1.12 (95% CI: 0.78-1.60) and 1.58 (95% CI: 1.10-2.26) for third to the first quartile of mtDNA copy numbers, respectively, comparing with the highest quartile (P for trend = 0.0135). The association varied little by the interval between blood draw and cancer diagnosis. To our knowledge, this is the first large prospective study evaluating the association of mtDNA copy number with subsequent risk of developing colorectal cancer. Our data suggests that decreased mtDNA copy number may be associated with increased colorectal cancer risk, and mtDNA copy number measured in peripheral blood cells may be a potential biomarker useful for colorectal cancer risk assessment.
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 1126. doi:1538-7445.AM2012-1126
Abstract 1134: Fumarate activates NRF2 in tissues with fumarate hydratase mutation
Authors: Ooi Aikseng , Whitten Douglas , Yang Ximing J. , Zhou Ming , Richard Stéphane , Teh Bin Tean , Furge Kyle A. 
Published: August 2012

Abstract
Fumarate hydratase (FH) mutation is associated with hereditary type 2 papillary renal cell carcinoma. Recently, we as well as others found that nuclear factor (erythroid-derived 2)-like 2 (NRF2) activation is a dominant feature of FH mutation. We demonstrate that in hereditary type 2 papillary renal cell carcinoma, fumarate covalently modified KEAP1 and leads to its ubiquitination. Consequently, NRF2 become activated. This predicts that similar mode of NRF2 activation may also be present in other tissues with FH mutation; overexpression of NRF2 target genes in various FH mutated tissues support the prediction that NRF2 is activated in these tissues. Variation in NRF2 targets expression may account for phenotypic differences among tumors associated with FH mutation.
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 1134. doi:1538-7445.AM2012-1134