Biochim. Biophys. Acta [JOURNAL]
Sun
200 papers
Probing the proton channels in subunit N of Complex I from Escherichia coli through intra-subunit cross-linking.
Tursun A, Zhu S, Vik SB
Biochim Biophys Acta · 2016 Dec · PMID 27632419 · Full text
Respiratory Complex I appears to have 4 sites for proton translocation, which are coupled to the oxidation of NADH and reduction of coenzyme Q. The proton pathways are thought to be made of offset half-channels that conn...
Respiratory Complex I appears to have 4 sites for proton translocation, which are coupled to the oxidation of NADH and reduction of coenzyme Q. The proton pathways are thought to be made of offset half-channels that connect to the membrane surfaces, and are connected by a horizontal path through the center of the membrane. In this study of the enzyme from Escherichia coli, subunit N, containing one of the sites, was targeted. Pairs of cysteine residues were introduced into neighboring α-helices along the proposed proton pathways. In an effort to constrain conformational changes that might occur during proton translocation, we attempted to form disulfide bonds or methanethiosulfonate bridges between two engineered cysteine residues. Cysteine modification was inferred by the inability of PEG-maleimide to shift the electrophoretic mobility of subunit N, which will occur upon reaction with free sulfhydryl groups. After the cross-linking treatment, NADH oxidase and NADH-driven proton translocation were measured. Ten different pairs of cysteine residues showed evidence of cross-linking. The most significant loss of enzyme activity was seen for residues near the essential Lys 395. This residue is positioned between the proposed proton half-channel to the periplasm and the horizontal connection through subunit N, and is also near the essential Glu 144 of subunit M. The results suggest important conformational changes in this region for the delivery of protons to the periplasm, or for coupling the actions of subunit N to subunit M.
Protein and lipid dynamics in photosynthetic thylakoid membranes investigated by in-situ solid-state NMR.
Azadi Chegeni F, Perin G, Sai Sankar Gupta KB … +3 more , Simionato D, Morosinotto T, Pandit A
Biochim Biophys Acta · 2016 Dec · PMID 27626974 · Publisher ↗
Photosynthetic thylakoid membranes contain the protein machinery to convert sunlight in chemical energy and regulate this process in changing environmental conditions via interplay between lipid, protein and xanthophyll...
Photosynthetic thylakoid membranes contain the protein machinery to convert sunlight in chemical energy and regulate this process in changing environmental conditions via interplay between lipid, protein and xanthophyll molecular constituents. This work addresses the molecular effects of zeaxanthin accumulation in thylakoids, which occurs in native systems under high light conditions through the conversion of the xanthophyll violaxanthin into zeaxanthin via the so called xanthophyll cycle. We applied biosynthetic isotope labeling and C solid-state NMR spectroscopy to simultaneously probe the conformational dynamics of protein, lipid and xanthophyll constituents of thylakoids isolated from wild type (cw15) and npq2 mutant of the green alga Chlamydomonas reinhardtii, that accumulates zeaxanthin constitutively. Results show differential dynamics of wild type and npq2 thylakoids. Ordered-phase lipids have reduced mobility and mobile-phase lipids have enlarged dynamics in npq2 membranes, together spanning a broader dynamical range. The fraction of ordered lipids is much larger than the fraction of mobile lipids, which explains why zeaxanthin appears to cause overall reduction of thylakoid membrane fluidity. In addition to the ordered lipids, also the xanthophylls and a subset of protein sites in npq2 thylakoids have reduced conformational dynamics. Our work demonstrates the applicability of solid-state NMR spectroscopy for obtaining a microscopic picture of different membrane constituents simultaneously, inside native, heterogeneous membranes.
A mathematical model of non-photochemical quenching to study short-term light memory in plants.
Matuszyńska A, Heidari S, Jahns P … +1 more , Ebenhöh O
Biochim Biophys Acta · 2016 Dec · PMID 27620066 · Publisher ↗
Plants are permanently exposed to rapidly changing environments, therefore it is evident that they had to evolve mechanisms enabling them to dynamically adapt to such fluctuations. Here we study how plants can be trained...
Plants are permanently exposed to rapidly changing environments, therefore it is evident that they had to evolve mechanisms enabling them to dynamically adapt to such fluctuations. Here we study how plants can be trained to enhance their photoprotection and elaborate on the concept of the short-term illumination memory in Arabidopsis thaliana. By monitoring fluorescence emission dynamics we systematically observe the extent of non-photochemical quenching (NPQ) after previous light exposure to recognise and quantify the memory effect. We propose a simplified mathematical model of photosynthesis that includes the key components required for NPQ activation, which allows us to quantify the contribution to photoprotection by those components. Due to its reduced complexity, our model can be easily applied to study similar behavioural changes in other species, which we demonstrate by adapting it to the shadow-tolerant plant Epipremnum aureum. Our results indicate that a basic mechanism of short-term light memory is preserved. The slow component, accumulation of zeaxanthin, accounts for the amount of memory remaining after relaxation in darkness, while the fast one, antenna protonation, increases quenching efficiency. With our combined theoretical and experimental approach we provide a unifying framework describing common principles of key photoprotective mechanisms across species in general, mathematical terms.
Electron transfer between carotenoid and chlorophyll contributes to quenching in the LHCSR1 protein from Physcomitrella patens.
Pinnola A, Staleva-Musto H, Capaldi S … +3 more , Ballottari M, Bassi R, Polívka T
Biochim Biophys Acta · 2016 Dec · PMID 27614061 · Publisher ↗
Plants harvest photons for photosynthesis using light-harvesting complexes (LHCs)-an array of chlorophyll proteins that can reversibly switch from harvesting to energy-dissipation mode to prevent over-excitation and dama...
Plants harvest photons for photosynthesis using light-harvesting complexes (LHCs)-an array of chlorophyll proteins that can reversibly switch from harvesting to energy-dissipation mode to prevent over-excitation and damage of the photosynthetic apparatus. In unicellular algae and lower plants this process requires the LHCSR proteins which senses over-acidification of the lumen trough protonatable residues exposed to the thylakoid lumen to activate quenching reactions. Further activation is provided by replacement of the violaxanthin ligand with its de-epoxidized product, zeaxanthin, also induced by excess light. We have produced the ppLHCSR1 protein from Physcomitrella patens by over-expression in tobacco and purified it in either its violaxanthin- or the zeaxanthin-binding form with the aim of analyzing their spectroscopic properties at either neutral or acidic pH. Using femtosecond spectroscopy, we demonstrated that the energy dissipation is achieved by two distinct quenching mechanism which are both activated by low pH. The first is present in both ppLHCSR1-Vio and ppLHCSR1-Zea and is characterized by 30-40ps time constant. The spectrum of the quenching product is reminiscent of a carotenoid radical cation, suggesting that the pH-induced quenching mechanism is likely electron transfer from the carotenoid to the excited Chl a. In addition, a second quenching channel populating the S state of carotenoid via energy transfer from Chl is found exclusively in the ppLHCSR1-Zea at pH5. These results provide proof of principle that more than one quenching mechanism may operate in the LHC superfamily and also help understanding the photoprotective role of LHCSR proteins and the evolution of LHC antennae.
Directed assembly of defined oligomeric photosynthetic reaction centres through adaptation with programmable extra-membrane coiled-coil interfaces.
Swainsbury DJ, Harniman RL, Di Bartolo ND … +4 more , Liu J, Harper WF, Corrie AS, Jones MR
Biochim Biophys Acta · 2016 Dec · PMID 27614060 · Full text
A challenge associated with the utilisation of bioenergetic proteins in new, synthetic energy transducing systems is achieving efficient and predictable self-assembly of individual components, both natural and man-made,...
A challenge associated with the utilisation of bioenergetic proteins in new, synthetic energy transducing systems is achieving efficient and predictable self-assembly of individual components, both natural and man-made, into a functioning macromolecular system. Despite progress with water-soluble proteins, the challenge of programming self-assembly of integral membrane proteins into non-native macromolecular architectures remains largely unexplored. In this work it is shown that the assembly of dimers, trimers or tetramers of the naturally monomeric purple bacterial reaction centre can be directed by augmentation with an α-helical peptide that self-associates into extra-membrane coiled-coil bundle. Despite this induced oligomerisation the assembled reaction centres displayed normal spectroscopic properties, implying preserved structural and functional integrity. Mixing of two reaction centres modified with mutually complementary α-helical peptides enabled the assembly of heterodimers in vitro, pointing to a generic strategy for assembling hetero-oligomeric complexes from diverse modified or synthetic components Addition of two coiled-coil peptides per reaction centre monomer was also tolerated despite the challenge presented to the pigment-protein assembly machinery of introducing multiple self-associating sequences. These findings point to a generalised approach where oligomers or longer range assemblies of multiple light harvesting and/or redox proteins can be constructed in a manner that can be genetically-encoded, enabling the construction of new, designed bioenergetic systems in vivo or in vitro.
Heterogeneity of Cancer Stem Cells: Rationale for Targeting the Stem Cell Niche.
Boesch M, Sopper S, Zeimet AG … +4 more , Reimer D, Gastl G, Ludewig B, Wolf D
Biochim Biophys Acta · 2016 Dec · PMID 27751894 · Full text
Malignancy is fuelled by distinct subsets of stem-like cells which persist under treatment and provoke drug-resistant recurrence. Eradication of these cancer stem cells has therefore become a prime objective for the deve...
Malignancy is fuelled by distinct subsets of stem-like cells which persist under treatment and provoke drug-resistant recurrence. Eradication of these cancer stem cells has therefore become a prime objective for the development and design of novel classes of anti-cancer therapeutics with improved clinical efficacy. Here, we portray potentially clinically-relevant hallmarks of cancer stem cells and focus on their recently appreciated properties of cell variability and plasticity, both of which make them elusive targets for cancer therapies. We reason that this 'disguise in heterogeneity' has fundamental implications for clinical management and elaborate on rational strategies to combat this diversity and target a broad range of tumorigenic cells. We propose exploitation of cancer stem cell niche dependence as a promising approach to interfere with various, rather than few, cancer stem cell subsets and suggest cancer-associated fibroblasts as a prime microenvironmental target for tumor stemness-depleting intervention.
Recent discoveries concerning the tumor - mesenchymal stem cell interactions.
Lazennec G, Lam PY
Biochim Biophys Acta · 2016 Dec · PMID 27750042 · Publisher ↗
Tumor microenvironment plays a crucial role in coordination with cancer cells in the establishment, growth and dissemination of the tumor. Among cells of the microenvironment, mesenchymal stem cells (MSCs) and their abil...
Tumor microenvironment plays a crucial role in coordination with cancer cells in the establishment, growth and dissemination of the tumor. Among cells of the microenvironment, mesenchymal stem cells (MSCs) and their ability to evolve into cancer associated fibroblasts (CAFs) have recently generated a major interest in the field. Numerous studies have described the potential pro- or anti-tumorigenic action of MSCs. The goal of this review is to synthesize recent and emerging discoveries concerning the mechanisms by which MSCs can be attracted to tumor sites, how they can generate CAFs and by which way MSCs are able to modulate the growth, response to treatments, angiogenesis, invasion and metastasis of tumors. The understanding of the role of MSCs in tumor development has potential and clinical applications in terms of cancer management.
Guidelines for the selection of functional assays to evaluate the hallmarks of cancer.
Menyhárt O, Harami-Papp H, Sukumar S … +4 more , Schäfer R, Magnani L, de Barrios O, Győrffy B
Biochim Biophys Acta · 2016 Dec · PMID 27742530 · Publisher ↗
The hallmarks of cancer capture the most essential phenotypic characteristics of malignant transformation and progression. Although numerous factors involved in this multi-step process are still unknown to date, an ever-...
The hallmarks of cancer capture the most essential phenotypic characteristics of malignant transformation and progression. Although numerous factors involved in this multi-step process are still unknown to date, an ever-increasing number of mutated/altered candidate genes are being identified within large-scale cancer genomic projects. Therefore, investigators need to be aware of available and appropriate techniques capable of determining characteristic features of each hallmark. We review the methods tailored to experimental cancer researchers to evaluate cell proliferation, programmed cell death, replicative immortality, induction of angiogenesis, invasion and metastasis, genome instability, and reprogramming of energy metabolism. Selecting the ideal method is based on the investigator's goals, available equipment and also on financial constraints. Multiplexing strategies enable a more in-depth data collection from a single experiment - obtaining several results from a single procedure reduces variability and saves time and relative cost, leading to more robust conclusions compared to a single end point measurement. Each hallmark possesses characteristics that can be analyzed by immunoblot, RT-PCR, immunocytochemistry, immunoprecipitation, RNA microarray or RNA-seq. In general, flow cytometry, fluorescence microscopy, and multiwell readers are extremely versatile tools and, with proper sample preparation, allow the detection of a vast number of hallmark features. Finally, we also provide a list of hallmark-specific genes to be measured in transcriptome-level studies. Although our list is not exhaustive, we provide a snapshot of the most widely used methods, with an emphasis on methods enabling the simultaneous evaluation of multiple hallmark features.
Novel mechanisms and approaches to overcome multidrug resistance in the treatment of ovarian cancer.
Ren F, Shen J, Shi H … +3 more , Hornicek FJ, Kan Q, Duan Z
Biochim Biophys Acta · 2016 Dec · PMID 27717733 · Publisher ↗
Ovarian cancer remains the leading cause of gynecological cancer-related mortality despite the advances in surgical techniques and chemotherapy drugs over the past three decades. Multidrug resistance (MDR) to chemotherap...
Ovarian cancer remains the leading cause of gynecological cancer-related mortality despite the advances in surgical techniques and chemotherapy drugs over the past three decades. Multidrug resistance (MDR) to chemotherapy is the major cause of treatment failure. Previous research has focused mainly on strategies to reverse MDR by targeting the MDR1 gene encoded P-glycoprotein (Pgp) with small molecular compound inhibitors. However, prior Pgp inhibitors have shown very limited clinical success because these agents have relatively low potency and high toxicity. Therefore, identification of more specific and potent new inhibitors would be useful. In addition, emerging evidence suggests that cancer stem cells (CSCs), deregulated non-coding RNA (ncRNA), autophagy, and tumor heterogeneity also contribute significantly to drug sensitivity/resistance in ovarian cancer. This review summarizes these novel mechanisms of MDR and evaluates several new concepts to overcome MDR in the treatment of ovarian cancer. These new strategies include overcoming MDR with more potent and specific Pgp inhibitors, targeting CSCs and ncRNA, modulating autophagy signaling pathway, and targeting tumor heterogeneity.
Pleiotrophin and its receptor protein tyrosine phosphatase beta/zeta as regulators of angiogenesis and cancer.
Papadimitriou E, Pantazaka E, Castana P … +3 more , Tsalios T, Polyzos A, Beis D
Biochim Biophys Acta · 2016 Dec · PMID 27693125 · Publisher ↗
Pleiotrophin (PTN) is a secreted heparin-binding growth factor that through its receptor protein tyrosine phosphatase beta/zeta (RPTPβ/ζ) has a significant regulatory effect on angiogenesis and cancer. PTN and RPTPβ/ζ ar...
Pleiotrophin (PTN) is a secreted heparin-binding growth factor that through its receptor protein tyrosine phosphatase beta/zeta (RPTPβ/ζ) has a significant regulatory effect on angiogenesis and cancer. PTN and RPTPβ/ζ are over-expressed in several types of human cancers and regulate important cancer cell functions in vitro and cancer growth in vivo. This review begins with a brief introduction of PTN and the regulation of its expression. PTN receptors are described with special emphasis on RPTPβ/ζ, which also interacts with and/or affects the function of other important targets for cancer therapy, such as vascular endothelial growth factor A, αβ and cell surface nucleolin. PTN biological activities related to angiogenesis and cancer are extensively discussed. Finally, up to date approaches of targeting PTN or RPTPβ/ζ for cancer treatment are presented. Insights into the regulatory role of PTN/RPTPβ/ζ on angiogenesis will be extremely beneficial for future development of alternative anti-angiogenic approaches in cancer therapy.
Functional characterization of AMP-activated protein kinase signaling in tumorigenesis.
Cheng J, Zhang T, Ji H … +3 more , Tao K, Guo J, Wei W
Biochim Biophys Acta · 2016 Dec · PMID 27681874 · Full text
AMP-activated protein kinase (AMPK) is a ubiquitously expressed metabolic sensor among various species. Specifically, cellular AMPK is phosphorylated and activated under certain stressful conditions, such as energy depri...
AMP-activated protein kinase (AMPK) is a ubiquitously expressed metabolic sensor among various species. Specifically, cellular AMPK is phosphorylated and activated under certain stressful conditions, such as energy deprivation, in turn to activate diversified downstream substrates to modulate the adaptive changes and maintain metabolic homeostasis. Recently, emerging evidences have implicated the potential roles of AMPK signaling in tumor initiation and progression. Nevertheless, a comprehensive description on such topic is still in scarcity, especially in combination of its biochemical features with mouse modeling results to elucidate the physiological role of AMPK signaling in tumorigenesis. Hence, we performed this thorough review by summarizing the tumorigenic role of each component along the AMPK signaling, comprising of both its upstream and downstream effectors. Moreover, their functional interplay with the AMPK heterotrimer and exclusive efficacies in carcinogenesis were chiefly explained among genetically altered mice models. Importantly, the pharmaceutical investigations of AMPK relevant medications have also been highlighted. In summary, in this review, we not only elucidate the potential functions of AMPK signaling pathway in governing tumorigenesis, but also potentiate the future targeted strategy aiming for better treatment of aberrant metabolism-associated diseases, including cancer.
The Cohesive Metastasis Phenotype in Human Prostate Cancer.
Harryman WL, Hinton JP, Rubenstein CP … +5 more , Singh P, Nagle RB, Parker SJ, Knudsen BS, Cress AE
Biochim Biophys Acta · 2016 Dec · PMID 27678419 · Full text
A critical barrier for the successful prevention and treatment of recurrent prostate cancer is detection and eradication of metastatic and therapy-resistant disease. Despite the fall in diagnoses and mortality, the repor...
A critical barrier for the successful prevention and treatment of recurrent prostate cancer is detection and eradication of metastatic and therapy-resistant disease. Despite the fall in diagnoses and mortality, the reported incidence of metastatic disease has increased 72% since 2004. Prostate cancer arises in cohesive groups as intraepithelial neoplasia, migrates through muscle and leaves the gland via perineural invasion for hematogenous dissemination. Current technological advances have shown cohesive-clusters of tumor (also known as microemboli) within the circulation. Circulating tumor cell (CTC) profiles are indicative of disseminated prostate cancer, and disseminated tumor cells (DTC) are found in cohesive-clusters, a phenotypic characteristic of both radiation- and drug-resistant tumors. Recent reports in cell biology and informatics, coupled with mass spectrometry, indicate that the integrin adhesome network provides an explanation for the biophysical ability of cohesive-clusters of tumor cells to invade thorough muscle and nerve microenvironments while maintaining adhesion-dependent therapeutic resistance. Targeting cohesive-clusters takes advantage of the known ability of extracellular matrix (ECM) adhesion to promote tumor cell survival and represents an approach that has the potential to avoid the progression to drug- and radiotherapy-resistance. In the following review we will examine the evidence for development and dissemination of cohesive-clusters in metastatic prostate cancer.
New Insights into Protein Hydroxylation and Its Important Role in Human Diseases.
Zurlo G, Guo J, Takada M … +2 more , Wei W, Zhang Q
Biochim Biophys Acta · 2016 Dec · PMID 27663420 · Full text
Protein hydroxylation is a post-translational modification catalyzed by 2-oxoglutarate-dependent dioxygenases. The hydroxylation modification can take place on various amino acids, including but not limited to proline, l...
Protein hydroxylation is a post-translational modification catalyzed by 2-oxoglutarate-dependent dioxygenases. The hydroxylation modification can take place on various amino acids, including but not limited to proline, lysine, asparagine, aspartate and histidine. A classical example of this modification is hypoxia inducible factor alpha (HIF-α) prolyl hydroxylation, which affects HIF-α protein stability via the Von-Hippel Lindau (VHL) tumor suppressor pathway, a Cullin 2-based E3 ligase adaptor protein frequently mutated in kidney cancer. In addition to protein stability regulation, protein hydroxylation may influence other post-translational modifications or the kinase activity of the modified protein (such as Akt and DYRK1A/B). In other cases, protein hydroxylation may alter protein-protein interaction and its downstream signaling events in vivo (such as OTUB1, MAPK6 and eEF2K). In this review, we highlight the recently identified protein hydroxylation targets and their pathophysiological roles, especially in cancer settings. Better understanding of protein hydroxylation will help identify novel therapeutic targets and their regulation mechanisms to foster development of more effective treatment strategies for various human cancers.
TIF-IA: An oncogenic target of pre-ribosomal RNA synthesis.
Jin R, Zhou W
Biochim Biophys Acta · 2016 Dec · PMID 27641688 · Full text
Cancer cells devote the majority of their energy consumption to ribosome biogenesis, and pre-ribosomal RNA transcription accounts for 30-50% of all transcriptional activity. This aberrantly elevated biological activity i...
Cancer cells devote the majority of their energy consumption to ribosome biogenesis, and pre-ribosomal RNA transcription accounts for 30-50% of all transcriptional activity. This aberrantly elevated biological activity is an attractive target for cancer therapeutic intervention if approaches can be developed to circumvent the development of side effects in normal cells. TIF-IA is a transcription factor that connects RNA polymerase I with the UBF/SL-1 complex to initiate the transcription of pre-ribosomal RNA. Its function is conserved in eukaryotes from yeast to mammals, and its activity is promoted by the phosphorylation of various oncogenic kinases in cancer cells. The depletion of TIF-IA induces cell death in lung cancer cells and mouse embryonic fibroblasts but not in several other normal tissue types evaluated in knock-out studies. Furthermore, the nuclear accumulation of TIF-IA under UTP down-regulated conditions requires the activity of LKB1 kinase, and LKB1-inactivated cancer cells are susceptible to cell death under such stress conditions. Therefore, TIF-IA may be a unique target to suppress ribosome biogenesis without significantly impacting the survival of normal tissues.
CRISPR-Cas9 therapeutics in cancer: promising strategies and present challenges.
Yi L, Li J
Biochim Biophys Acta · 2016 Dec · PMID 27641687 · Publisher ↗
Cancer is characterized by multiple genetic and epigenetic alterations that drive malignant cell proliferation and confer chemoresistance. The ability to correct or ablate such mutations holds immense promise for combati...
Cancer is characterized by multiple genetic and epigenetic alterations that drive malignant cell proliferation and confer chemoresistance. The ability to correct or ablate such mutations holds immense promise for combating cancer. Recently, because of its high efficiency and accuracy, the CRISPR-Cas9 genome editing technique has been widely used in cancer therapeutic explorations. Several studies used CRISPR-Cas9 to directly target cancer cell genomic DNA in cellular and animal cancer models which have shown therapeutic potential in expanding our anticancer protocols. Moreover, CRISPR-Cas9 can also be employed to fight oncogenic infections, explore anticancer drugs, and engineer immune cells and oncolytic viruses for cancer immunotherapeutic applications. Here, we summarize these preclinical CRISPR-Cas9-based therapeutic strategies against cancer, and discuss the challenges and improvements in translating therapeutic CRISPR-Cas9 into clinical use, which will facilitate better application of this technique in cancer research. Further, we propose potential directions of the CRISPR-Cas9 system in cancer therapy.
Metabolic plasticity in heterogeneous pancreatic ductal adenocarcinoma.
Liang C, Qin Y, Zhang B … +10 more , Ji S, Shi S, Xu W, Liu J, Xiang J, Liang D, Hu Q, Ni Q, Xu J, Yu X
Biochim Biophys Acta · 2016 Dec · PMID 27600832 · Publisher ↗
Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal malignant neoplasms. The recognized hallmarks of PDA are regarded to be downstream events of metabolic reprogramming. Because PDA is a heterogeneous diseas...
Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal malignant neoplasms. The recognized hallmarks of PDA are regarded to be downstream events of metabolic reprogramming. Because PDA is a heterogeneous disease that is influenced by genetic polymorphisms and changes in the microenvironment, metabolic plasticity is a novel feature of PDA. As intrinsic factors for metabolic plasticity, K-ras activation and mutations in other tumor suppressor genes induce abnormal mitochondrial metabolism and enhance glycolysis, with alterations in glutamine and lipid metabolism. As extrinsic factors, the acidic and oxygen/nutrient-deprived microenvironment also induces cancer cells to reprogram their metabolic pathway and hijack stromal cells (mainly cancer-associated fibroblasts and immunocytes) to communicate, thereby adapting to metabolic stress. Therefore, a better understanding of the metabolic features of PDA will contribute to the development of novel diagnostic and therapeutic strategies.
Aspirin in pancreatic cancer: chemopreventive effects and therapeutic potentials.
Jiang MJ, Dai JJ, Gu DN … +2 more , Huang Q, Tian L
Biochim Biophys Acta · 2016 Dec · PMID 27567928 · Publisher ↗
Pancreatic cancer is one of the most aggressive malignancies with dismal prognosis. Recently, aspirin has been found to be an effective chemopreventive agent for many solid tumors. However, the function of aspirin use in...
Pancreatic cancer is one of the most aggressive malignancies with dismal prognosis. Recently, aspirin has been found to be an effective chemopreventive agent for many solid tumors. However, the function of aspirin use in pancreatic cancer largely remains unknown. We herein argued that aspirin could also lower the risk of pancreatic cancer. Importantly, aspirin assumes pleiotropic effects by targeting multiple molecules. It could further target the unique tumor biology of pancreatic cancer and modify the cancer microenvironment, thus showing remarkable therapeutic potentials. Besides, aspirin could reverse the chemoradiation resistance by repressing tumor repopulation and exert synergistic potentials with metformin on pancreatic cancer chemoprevention. Moreover, aspirin secondarily benefits pancreatic cancer patients through modestly reducing cancer pain and the risk of venous thromboembolism. Furthermore, new aspirin derivatives and delivery systems might help to improve risk-to-benefit ratio. In brief, aspirin is a promising chemopreventive agent and exerts significant therapeutic potentials in pancreatic cancer.
Mechanism of antineoplastic activity of lonidamine.
Nath K, Guo L, Nancolas B … +9 more , Nelson DS, Shestov AA, Lee SC, Roman J, Zhou R, Leeper DB, Halestrap AP, Blair IA, Glickson JD
Biochim Biophys Acta · 2016 Dec · PMID 27497601 · Full text
Lonidamine (LND) was initially introduced as an antispermatogenic agent. It was later found to have anticancer activity sensitizing tumors to chemo-, radio-, and photodynamic-therapy and hyperthermia. Although the mechan...
Lonidamine (LND) was initially introduced as an antispermatogenic agent. It was later found to have anticancer activity sensitizing tumors to chemo-, radio-, and photodynamic-therapy and hyperthermia. Although the mechanism of action remained unclear, LND treatment has been known to target metabolic pathways in cancer cells. It has been reported to alter the bioenergetics of tumor cells by inhibiting glycolysis and mitochondrial respiration, while indirect evidence suggested that it also inhibited l-lactic acid efflux from cells mediated by members of the proton-linked monocarboxylate transporter (MCT) family and also pyruvate uptake into the mitochondria by the mitochondrial pyruvate carrier (MPC). Recent studies have demonstrated that LND potently inhibits MPC activity in isolated rat liver mitochondria (K 2.5μM) and cooperatively inhibits l-lactate transport by MCT1, MCT2 and MCT4 expressed in Xenopus laevis oocytes with K and Hill coefficient values of 36-40μM and 1.65-1.85, respectively. In rat heart mitochondria LND inhibited the MPC with similar potency and uncoupled oxidation of pyruvate was inhibited more effectively (IC~7μM) than other substrates including glutamate (IC~20μM). LND inhibits the succinate-ubiquinone reductase activity of respiratory Complex II without fully blocking succinate dehydrogenase activity. LND also induces cellular reactive oxygen species through Complex II and has been reported to promote cell death by suppression of the pentose phosphate pathway, which resulted in inhibition of NADPH and glutathione generation. We conclude that MPC inhibition is the most sensitive anti-tumour target for LND, with additional inhibitory effects on MCT-mediated l-lactic acid efflux, Complex II and glutamine/glutamate oxidation.
Human papillomavirus in oropharyngeal cancer: The changing face of a disease.
Mallen-St Clair J, Alani M, Wang MB … +1 more , Srivatsan ES
Biochim Biophys Acta · 2016 Dec · PMID 27487173 · Publisher ↗
The last decade has brought about an unexpected rise in oropharyngeal squamous cell carcinoma (OPSCC) primarily in white males from the ages of 40-55years, with limited exposure to alcohol and tobacco. This subset of squ...
The last decade has brought about an unexpected rise in oropharyngeal squamous cell carcinoma (OPSCC) primarily in white males from the ages of 40-55years, with limited exposure to alcohol and tobacco. This subset of squamous cell carcinoma (SCC) has been found to be associated with human papillomavirus infection (HPV). Other Head and Neck Squamous Cell carcinoma (HNSCC) subtypes include oral cavity, hypopharyngeal, nasopharyngeal, and laryngeal SCC which tend to be HPV negative. HPV associated oropharyngeal cancer has proven to differ from alcohol and tobacco associated oropharyngeal carcinoma in regards to the molecular pathophysiology, presentation, epidemiology, prognosis, and improved response to chemoradiation therapy. Given the improved survival of patients with HPV associated SCC, efforts to de-intensify treatment to decrease treatment related morbidity are at the forefront of clinical research. This review will focus on the important differences between HPV and tobacco related oropharyngeal cancer. We will review the molecular pathogenesis of HPV related oropharyngeal cancer with an emphasis on new paradigms for screening and treating this disease.
Means to the ends: The role of telomeres and telomere processing machinery in metastasis.
Robinson NJ, Schiemann WP
Biochim Biophys Acta · 2016 Dec · PMID 27768860 · Full text
Despite significant clinical advancements, cancer remains a leading cause of mortality throughout the world due largely to the process of metastasis and the dissemination of cancer cells from their primary tumor of origi...
Despite significant clinical advancements, cancer remains a leading cause of mortality throughout the world due largely to the process of metastasis and the dissemination of cancer cells from their primary tumor of origin to distant secondary sites. The clinical burden imposed by metastasis is further compounded by a paucity of information regarding the factors that mediate metastatic progression. Linear chromosomes are capped by structures known as telomeres, which dictate cellular lifespan in humans by shortening progressively during successive cell divisions. Although telomere shortening occurs in nearly all somatic cells, telomeres may be elongated via two seemingly disjoint pathways: (i) telomerase-mediated extension, and (ii) homologous recombination-based alternative lengthening of telomeres (ALT). Both telomerase and ALT are activated in various human cancers, with more recent evidence implicating both pathways as potential mediators of metastasis. Here we review the known roles of telomere homeostasis in metastasis and posit a mechanism whereby metastatic activity is determined by a dynamic fluctuation between ALT and telomerase, as opposed to the mere activation of a generic telomere elongation program. Additionally, the pleiotropic nature of the telomere processing machinery makes it an attractive therapeutic target for metastasis, and as such, we also explore the therapeutic implications of our proposed mechanism.
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