Cancer Cell Biology

Mitochondrial NADH-dehydrogenase polymorphisms as sporadic breast cancer risk factor.

by Anna M. Czarnecka

Breast cancer is the most frequently diagnosed
female cancer all over the world. Although the molecularmore Breast cancer is the most frequently diagnosed
female cancer all over the world. Although the molecular
genetics of this disease has been the focus of many projects
for over 20 years, the number of prognostic markers used in
clinics is still unsatisfactory. Mitochondrial DNA mutations
have been reported in many breast cancer studies. To
investigate the possible role of mitochondrial inherited
polymorphisms in breast cancer development we analyzed
the sequence of NADH-dehydrogenase genes in cancer
samples and their corresponding normal tissues. We detected
increased incidence of mtDNA polymorphisms, in particular
very rare polymorphisms such as A4727G, G9947A,
A10044G, A10283G, T11233C, and C11503T. Our report
supports the notion that mtDNA polymorphisms establish a
specific genetic background for breast cancer development
and that mtDNA analysis may help in selection of cohorts
that should undergo intensive screening and early detection
programs

Dynamic Mitochondrial Networks in Cancer

by Jalees Rehman

Published on the Scientific American Blog

Research projects evolve in a fortuitous manner, often guided by a convergence of novel observations, intuition,... more Research projects evolve in a fortuitous manner, often guided by a convergence of novel observations, intuition, helpful colleagues and unique personal circumstances. It is precisely this constellation that prompted two cardiologists to study the mitochondrial networks in lung cancer cells.

In 2008, my colleague and friend Stephen Archer, a Professor of Medicine at the University of Chicago, asked me whether I would be interested in studying the role of mitochondrial networks in lung cancer cells. My first response was the question “Do mitochondria really form networks?”, because at that time the expression “mitochondria” evoked images of scattered oval-like organelles, a textbook image of electron microscopy.......

Computational Identification and Modeling of Crosstalk between Phosphorylation, O-β-glycosylation and Methylation of FoxO3 and Implications for Cancer Therapeutics

by Azeem Butt

Published in International Journal of Molecular Sciences

Hypericum perforatum Extracts and Hypericin Treatment of a Mouse Mammary Cancer Cell Line Induces Growth Inhibition in a Dose Dependent Manner

by Ravi Dinakar

For free pdf paper visit:

http://www.jes2s.com/pdfs/Jan2012/Hypericum%20perforatum%20Extracts%20and%20Hypericin%20Treatment%20of%20a%20Mouse%20Mammary%20Cancer%20Cell%20Line%20Induces%20Growth%20Inhibition%20in%20a%20Dose%20Dependent%20Manner.pdf

Authors:

Ashley Ferguson1*, Caitlin Morris1*, and Jackie Curley2
Student1, Teacher2: The Loudoun County Academy of Science, Sterling VA
*these authors contributed equally.
*correspondence: ashleyferguson7@aol.com; camorris94@gmail.com

Hypericum perforatum, commonly known as St. John’s
Wort, has been found to exhibit many medicinal, especiallymore Hypericum perforatum, commonly known as St. John’s
Wort, has been found to exhibit many medicinal, especially
anti-depressant, properties. Hypericin is thought to be the
main chemical constituent responsible for H. perforatum’s
medicinal properties. We report here the ability of H.
perforatum and hypericin to inhibit the growth of mouse
mammary cancer CRL2539 cells. H. perforatum, at
concentrations of 0.4% and 0.8%, significantly (P<0.05)
inhibited cell growth in a concentration dependent manner.
Hypericin (purity 80-90%) at a concentration of 0.001%
also significantly inhibited cell growth but not to the extent
which the H. perforatum extracts did. In addition, H.
perforatum at a concentration of 0.8% inhibited cell growth
significantly more than H. perforatum at a concentration
of 0.4%. Our study shows a promising therapeutic strategy
in using the whole H. perforatum extract as its own form
of treatment to effectively slow the growth rate of cancer
cells, and potentially overcome the negative side effects
associated with current forms of cancer treatment.

Survivin is Essential for Efficient Cell Mobility and Proliferation in U87 and C6 Glioma Cells

by Ravi Dinakar

For FREE full pdf visit:

http://www.jes2s.com/pdfs/Jan2012/Survivin%20is%20Essential%20for%20Efficient%20Cell%20Mobility%20and%20Proliferation%20in%20U87%20and%20C6%20Glioma%20Cells.pdf

Authors:

Miguel Santiago Montana1* and Christine Marshall-Walker2
Student1, Teacher2: Phillips Academy Andover, 180 Main Street Andover, MA 01810
*Correspondence: m.montana@umiami.edu

Published in The Journal of Experimental Secondary Science (www.jes2s.com)

The BIRC5 gene, which codes for Survivin and is a member
of the Inhibitor of Apoptosis family, is activated in... more The BIRC5 gene, which codes for Survivin and is a member
of the Inhibitor of Apoptosis family, is activated in most
cancer cells including gliomas. The BIRC5 gene’s role in
cancer motility is not well understood. From the functions
of similar genes, like those in its family, it was hypothesized
that the gene would play an important role in cancer
motility as well as cancer proliferation1. The BIRC5 gene’s
importance in migration and proliferation was studied in
rat C6 and human U87 glioma cells. The gene’s importance
in migration was assessed by observing the migration
behaviors of four groups of cells: an experimental group
that was transfected with BIRC5 siRNA and permitted to
grow for one day after transfection, another experimental
group that was permitted to grow for two days after
transfection, and two corresponding control groups that
did not undergo RNAi of BIRC5 and were permitted to
grow for one and two days. The control groups exhibited
near-equal levels of migration when a migration assay was
performed. Both groups that underwent RNAi of BIRC5
showed impaired migratory ability. When proliferation
was analyzed for the same groups, the cells that underwent
RNAi showed diminished ability to reproduce and survive,
especially when they were plated at lower densities. These
results suggest Survivin is a promising drug target in the
control of glioma cell motility and proliferation.

Persistent competition among stem cells and their daughters in the Drosophila ovary germline niche

by Eduardo Moreno Lampaya

Moreno and Basler, Cell 2004

by Eduardo Moreno Lampaya

Super competition as a possible mechanism to pioneer precancerous fields

by Eduardo Moreno Lampaya

Inhibition of mitochondrial fission prevents cell cycle progression in lung cancer

by Jalees Rehman

Published in the FASEB Journal

Mitochondria exist in dynamic networks that undergo fusion and fission. Mitochondrial fusion and fission are mediated... more Mitochondria exist in dynamic networks that undergo fusion and fission. Mitochondrial fusion and fission are mediated by several GTPases in the outer mitochondrial membrane, notably mitofusin-2 (Mfn-2), which promotes fusion, and dynamin-related protein (Drp-1), which promotes fission. We report that human lung cancer cell lines exhibit an imbalance of Drp-1/Mfn-2 expression, which promotes a state of mitochondrial fission. Lung tumor tissue samples from patients demonstrated a similar increase in Drp-1 and decrease in Mfn-2 when compared to adjacent healthy lung. Complementary approaches to restore mitochondrial network formation in lung cancer cells by overexpression of Mfn-2, Drp-1 inhibition, or Drp-1 knockdown resulted in a marked reduction of cancer cell proliferation and an increase in spontaneous apoptosis. The number of cancer cells in S phase decreased from 32.4 ± 0.6 to 6.4 ± 0.3% with Drp-1 inhibition (P<0.001). In a xenotransplantation model, Mfn-2 gene therapy or Drp-1 inhibition could regress tumor growth. The tumor volume decreased from 205.6 ± 59 to 70.6 ± 15 mm(3) (P<0.05) with Mfn-2 overexpression and from 186.0 ± 19 to 87.0 ± 6 mm(3) (P<0.01) with therapeutic Drp-1 inhibition. Impaired fusion and enhanced fission contribute fundamentally to the proliferation/apoptosis imbalance in cancer and constitute promising novel therapeutic targets.

Cancer Networks: A general theoretical and computational framework for understanding cancer

by Eric Werner

Published on arxiv.org Oct 26, 2011:
http://arxiv.org/abs/1110.5865

We present a general computational theory of cancer and its developmental dynamics. The theory is based on a theory of... more We present a general computational theory of cancer and its developmental dynamics. The theory is based on a theory of the architecture and function of developmental control networks which guide the formation of multicellular organisms. Cancer networks are special cases of developmental control networks. Cancer results from transformations of normal developmental networks. Our theory generates a natural classification of all possible cancers based on their network architecture. Each cancer network has a unique topology and semantics and developmental dynamics that result in distinct clinical tumor phenotypes. We apply this new theory with a series of proof of concept cases for all the basic cancer types. These cases have been computationally modeled, their behavior simulated and mathematically described using a multicellular systems biology approach. There are fascinating correspondences between the dynamic developmental phenotype of computationally modeled in silico cancers and natural in vivo cancers. The theory lays the foundation for a new research paradigm for understanding and investigating cancer. The theory of cancer networks implies that new diagnostic methods and new treatments to cure cancer will become possible.

Germline mutations in DIS3L2 cause the Perlman syndrome of overgrowth and Wilms tumor susceptibility

by Mark Morris

Dewi Astuti & Mark R Morris, Wendy N Cooper,  Raymond H J Staals, Naomi C Wake,  Graham A Fews, Harmeet Gill,  Dean Gentle,  Salwati Shuib, Christopher J Ricketts, Trevor Cole,  Anthonie J van Essen, Richard A van Lingen,  Giovanni Neri,  John M Opitz, Patrick Rump, Irene Stolte-Dijkstra, Ferenc Müller, Ger J M Pruijn, Farida Latif & Eamonn R Maher

Perlman syndrome is a congenital overgrowth syndrome inherited in an autosomal recessive manner that is associated... more Perlman syndrome is a congenital overgrowth syndrome inherited in an autosomal recessive manner that is associated with Wilms tumor susceptibility. We mapped a previously unknown susceptibility locus to 2q37.1 and identified germline mutations in DIS3L2, a homolog of the Schizosaccharomyces pombe dis3 gene, in individuals with Perlman syndrome. Yeast dis3 mutant strains have mitotic abnormalities. Yeast Dis3 and its human homologs, DIS3 and DIS3L1, have exoribonuclease activity and bind to the core RNA exosome complex. DIS3L2 has a different intracellular localization and lacks the PIN domain found in DIS3 and DIS3L1; nevertheless, we show that DIS3L2 has exonuclease activity. DIS3L2 inactivation was associated with mitotic abnormalities and altered expression of mitotic checkpoint proteins. DIS3L2 overexpression suppressed the growth of human cancer cell lines, and knockdown enhanced the growth of these cells. We also detected evidence of DIS3L2 mutations in sporadic Wilms tumor. These observations suggest that DIS3L2 has a critical role in RNA metabolism and is essential for the regulation of cell growth and division.

Regular Articles-Cell Biology-Automated Electrorotation to Reveal Dielectric Variations Related to HER-2/neu Overexpression in MCF-7 Sublines.

by Giovanni De Gasperis

Changes in oligosaccharide chains of autoantibodies to GRP78 expressed during progression of malignant melanoma stimulate melanoma cell growth and survival

by Gustaaf de Ridder

Modulation of the Unfolded Protein Response by GRP78 in Prostate Cancer.

by Gustaaf de Ridder

HURP permits MTOC sorting for robust meiotic spindle bipolarity, similar to extra centrosome clustering in cancer cells

by Manuel Breuer

The benzoquinone ansamycin 17-allylamino-17-demethoxygeldanamycin binds to HSP90 and shares important biologic activities with geldanamycin

by Robert Bradley

1H NMR metabolomics combined with gene expression analysis for the determination of major metabolic differences between subtypes of breast cell lines

by Dan Tulpan

Cuperlovic-Culf, M., Chute, I.C., Culf, A.S., Touaibia, M., Ghosh, A., Griffiths, S., Tulpan, D., Léger, S., Belkaid, A., Surette, M.E., Ouellette, R.J. (2011). 1H NMR metabolomics combined with gene expression analysis for the determination of major metabolic differences between subtypes of breast cell lines. Chemical Science, 2, 2263-2270.

1H NMR analysis was performed on metabolic extracts from a selection of six breast cell lines, including... more 1H NMR analysis was performed on metabolic extracts from a selection of six breast cell lines, including normal-immortalized, invasive ductal carcinomas and adenocarcinomas. Metabolites with significant concentration differences between normal and cancerous cells as well as ER+ and ER− (estrogen receptor) cells were determined and their relation to the differentially expressed genes was explored. Major differences have been shown for many amino acids and this was linked to expression level changes of related genes. Observed changes in choline concentration were connected to expression level changes of the SCL44A1 transporter gene.

The HDAC inhibitor panobinostat (LBH589) inhibits mesothelioma and lung cancer cells in vitro and in vivo with particular efficacy for small cell lung cancer.

by Dr. Gary Kao and Dr. Jay Dorsey

Crisanti MC, Wallace AF, Kapoor V, Vandermeers F, Dowling ML, Pereira LP, Coleman K, Campling BG, Fridlender ZG, Kao GD, Albelda SM.
SourceThoracic Oncology Research Laboratory, University of Pennsylvania, Philadelphia, USA.

Lung cancer is the leading cause of cancer deaths in the United States. Current therapies are inadequate. Histone... more Lung cancer is the leading cause of cancer deaths in the United States. Current therapies are inadequate. Histone deacetylase inhibitors (HDACi) are a recently developed class of anticancer agents that cause increased acetylation of core histones and nonhistone proteins leading to modulation of gene expression and protein activity involved in cancer cell growth and survival pathways. We examined the efficacy of the HDACi panobinostat (LBH589) in a wide range of lung cancers and mesotheliomas. Panobinostat was cytotoxic in almost all 37 cancer cell lines tested. IC(50) and LD(50) values were in the low nmol/L range (4-470 nmol/L; median, 20 nmol/L). Small cell lung cancer (SCLC) cell lines were among the most sensitive lines, with LD(50) values consistently <25 nmol/L. In lung cancer and mesothelioma animal models, panobinostat significantly decreased tumor growth by an average of 62% when compared with vehicle control. Panobinostat was equally effective in immunocompetent and severe combined immunodeficiency mice, indicating that the inhibition of tumor growth by panobinostat was not due to direct immunologic effects. Panobinostat was, however, particularly effective in SCLC xenografts, and the addition of the chemotherapy agent etoposide augmented antitumor effects. Protein analysis of treated tumor biopsies revealed elevated amounts of cell cycle regulators such as p21 and proapoptosis factors, such as caspase 3 and 7 and cleaved poly[ADP-ribose] polymerase, coupled with decreased levels of antiapoptotic factors such as Bcl-2 and Bcl-X(L). These studies together suggest that panobinostat may be a useful adjunct in the treatment of thoracic malignancies, especially SCLC.

Repression of mitogen-activated protein kinases ERK1/ERK2 activity by a protein tyrosine phosphatase in rat fibroblasts transformed by upstream oncoproteins

by Kailesh Gopalbhai

Kailesh Gopalbhai and Sylvain Meloche, Journal of cellular physiology 1998; 174(1) :35-47

The observation that mitogen-activated protein (MAP) kinases ERK1 and ERK2 are constitutively activated in a number of... more The observation that mitogen-activated protein (MAP) kinases ERK1 and ERK2 are constitutively activated in a number of oncogene-transformed cell lines has led to the hypothesis that prolonged activation of these enzymes is required for the transformation process. To investigate this question, we have examined the regulation of the ERK pathway in Rat1 fibroblasts transformed with activated c-Raf-1 (Raf22W), v-Ha-Ras, and v-Src. Expression of these oncoproteins had no effect on the enzymatic activity of ERK1 and ERK2 in either serum-starved or exponentially growing cells. Moreover, the stimulatory effect of serum on ERK1/ERK2 activity was substantially reduced or abrogated in these cells; this impairment was associated with a strong attenuation of c-fos gene induction. In contrast, expression of Raf22w, v-Ha-Ras, or v-Src resulted in the constitutive activation of the upstream kinases MEK1 and MEK2. Treatment of the cells with vanadate completely restored the activation of ERK1/ERK2 in oncogene-transformed cells, suggesting the involvement of a vanadate-sensitive tyrosine phosphatase. Northern blot analysis of VH1-like dual-specificity MAP kinase phosphatases did not reveal any significant difference in the mRNA expression pattern of these genes between parental and transformed Rat1 cells. Phosphoamino acid analysis indicated that ERK1 is phosphorylated on threonine, but not on tyrosine, in oncogene-transformed cells and that vanadate treatment restores tyrosine phosphorylation. We conclude from these results that ERK1/ERK2 activity is repressed by a single-specificity tyrosine phosphatase in oncogene-transformed rat fibroblasts.

Mitochondrial failure in cell transformation

by Anna M. Czarnecka

For many years mitochondria have been implicated in the process of carcinogenesis. At the begining of 20th century... more For many years mitochondria have been implicated in the process of carcinogenesis. At the begining of 20th century Otto Warburg has started research focused on failure of oxidative metabolism in cancer cells. In his work he described „disruption of respiration” as typical for cancer cells. Warburg’s discovery resulted in establishment of many projects focused on the role of mitochondria in cell transformation. Since that time multiple research groups have reported mitochondria DNA mutations in majority of cancer types. Recently re-analyses of raw data has been published and have shown multiple methodical errors in previous reports. This paper  presents critical analysis and summary of mitochondria polymorphisms and somatic mutations research in oncology.
Literature analysis that includes latest methodological guidelines established for mtDNA analysis and evidence based medicine reports proves that cancer patients harbour specific pattern of inherited mtDNA polymorphisms and low numer of somatic mutations. It seems that mitochondrial genotype (including haplotype) may be classified as cancer predisposing factor. 


KEY WORDS
cancer, molecular marker, mitochondria, mtDNA mutation, mtDNA polymorphism, Evidence Based Medicine