66 research outputs found
Analysis of the functional repertoire of a mutant form of survivin, K129E, which has been linked to lung cancer
Background
Survivin is a protein that is normally present only in G2 and M-phases in somatic cells, however, in cancer cells, it is expressed throughout the cell cycle. A prosurvival factor, survivin is both an inhibitor of apoptosis and an essential mitotic protein, thus it has attracted much attention as a target for new oncotherapies. Despite its prevalence in cancer, reports of survivin mutations have mostly been restricted to loci within its promoter, which increase the abundance of the protein. To date the only published mutation within the coding sequence is an adenine > guanine substitution in exon 4. This polymorphism, which was found in a cohort of Korean lung cancer patients, causes a lysine > glutamic acid mutation (K129E) in the protein. However, whether it plays a causative role in cancer has not been addressed.
Methods
Using site directed mutagenesis we recapitulate K129E expression in cultured human cells and assess its anti-apoptotic and mitotic activities.
Results
K129E retains its anti-apoptotic activity, but causes errors in mitosis and cytokinesis, which may be linked to its reduced affinity for borealin.
Conclusion
K129E expression can induce genomic instability by introducing mitotic aberrations, thus it may play a causative role in cancer
Improving the Prognostic Ability through Better Use of Standard Clinical Data - The Nottingham Prognostic Index as an Example
Background Prognostic factors and prognostic models play a key role in medical
research and patient management. The Nottingham Prognostic Index (NPI) is a
well-established prognostic classification scheme for patients with breast
cancer. In a very simple way, it combines the information from tumor size,
lymph node stage and tumor grade. For the resulting index cutpoints are
proposed to classify it into three to six groups with different prognosis. As
not all prognostic information from the three and other standard factors is
used, we will consider improvement of the prognostic ability using suitable
analysis approaches. Methods and Findings Reanalyzing overall survival data of
1560 patients from a clinical database by using multivariable fractional
polynomials and further modern statistical methods we illustrate suitable
multivariable modelling and methods to derive and assess the prognostic
ability of an index. Using a REMARK type profile we summarize relevant steps
of the analysis. Adding the information from hormonal receptor status and
using the full information from the three NPI components, specifically
concerning the number of positive lymph nodes, an extended NPI with improved
prognostic ability is derived. Conclusions The prognostic ability of even one
of the best established prognostic index in medicine can be improved by using
suitable statistical methodology to extract the full information from standard
clinical data. This extended version of the NPI can serve as a benchmark to
assess the added value of new information, ranging from a new single clinical
marker to a derived index from omics data. An established benchmark would also
help to harmonize the statistical analyses of such studies and protect against
the propagation of many false promises concerning the prognostic value of new
measurements. Statistical methods used are generally available and can be used
for similar analyses in other diseases
Lactate/pyruvate transporter MCT-1 is a direct Wnt target that confers sensitivity to 3-bromopyruvate in colon cancer
BACKGROUND: There is increasing evidence that oncogenic Wnt signaling directs metabolic reprogramming of cancer cells to favor aerobic glycolysis or Warburg metabolism. In colon cancer, this reprogramming is due to direct regulation of pyruvate dehydrogenase kinase 1 (PDK1) gene transcription. Additional metabolism genes are sensitive to Wnt signaling and exhibit correlative expression with PDK1. Whether these genes are also regulated at the transcriptional level, and therefore a part of a core metabolic gene program targeted by oncogenic WNT signaling, is not known. RESULTS: Here, we identify monocarboxylate transporter 1 (MCT-1; encoded by SLC16A1) as a direct target gene supporting Wnt-driven Warburg metabolism. We identify and validate Wnt response elements (WREs) in the proximal SLC16A1 promoter and show that they mediate sensitivity to Wnt inhibition via dominant-negative LEF-1 (dnLEF-1) expression and the small molecule Wnt inhibitor XAV939. We also show that WREs function in an independent and additive manner with c-Myc, the only other known oncogenic regulator of SLC16A1 transcription. MCT-1 can export lactate, the byproduct of Warburg metabolism, and it is the essential transporter of pyruvate as well as a glycolysis-targeting cancer drug, 3-bromopyruvate (3-BP). Using sulforhodamine B (SRB) assays to follow cell proliferation, we tested a panel of colon cancer cell lines for sensitivity to 3-BP. We observe that all cell lines are highly sensitive and that reduction of Wnt signaling by XAV939 treatment does not synergize with 3-BP, but instead is protective and promotes rapid recovery. CONCLUSIONS: We conclude that MCT-1 is part of a core Wnt signaling gene program for glycolysis in colon cancer and that modulation of this program could play an important role in shaping sensitivity to drugs that target cancer metabolism. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s40170-016-0159-3) contains supplementary material, which is available to authorized users
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