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Luciferase fragment complementation imaging in preclinical cancer studies

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Luciferase fragment complementation imaging in preclinical cancer studies ABSTRACT The luciferase fragment complementation assay (LFCA) enables molecular events to be non-invasively imaged in live cells  in vitro  and  in vivo  in a comparatively cheap and safe manner. It is a development of previous enzyme complementation assays in which reporter genes are split into two, individually enzymatically inactive, fragments that are able to complement one another upon interaction. This complementation can be used to externally visualize cellular activities. In recent years, the number of studies which have used LFCAs to probe questions relevant to cancer have increased, and this review summarizes the most significant and interesting of these. In particular, it focuses on work conducted on the epidermal growth factor, nuclear and chemokine receptor families, and intracellular signaling pathways, including IP 3 , cAMP, Akt, cMyc, NRF2 and Rho GTPases. LFCAs which have been developed to image
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Immuno-stimultory/regulatory gene expression patterns in advanced ovarian cancer

Immuno-stimultory/regulatory gene expression patterns in advanced ovarian cancer ABSTRACT It has been established that a high degree of tumor-infiltrating T cells is associated with ovarian cancer prognosis. We hypothesized that tumors display an immune-related program of transcription that can act in a stimulatory or a regulatory manner. We analyzed transcriptome-wide gene expression data from 503 ovarian tumors from the Cancer Genome Atlas to identify genes that show differential prognoses when stratified by CD3 expression. Genes with immunological functions and tumor antigen genes were selected for analysis. We repeated our analysis in an independent validation study. Five genes showed stimulatory/regulatory patterns at a high level of confidence (Bonferroni p < 0.05). Three of these (MAGEA8, MPL, AMHR2) were validated and one (WT1) could not be evaluated. These patterns show specific prognostic effect only in conjunction with CD3 expression. When patients express multiple transc
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High expression of cellular retinol binding protein-1 in lung adenocarcinoma is associated with poor prognosis

High expression of cellular retinol binding protein-1 in lung adenocarcinoma is associated with poor prognosis ABSTRACT Purpose: Adenocarcinoma, the most common non-small cell lung cancer is a leading cause of death worldwide, with a low overall survival (OS) despite increasing attempts to achieve an early diagnosis and accomplish surgical and multimodality treatment strategies. Cellular retinol binding protein-1 (CRBP-1) regulates retinol bioavailability and cell differentiation, but its role in lung cancerogenesis remains uncertain. Experimental design: CRBP-1 expression, clinical outcome and other prognostic factors were investigated in 167 lung adenocarcinoma patients. CRBP-1 expression was evaluated by immunohistochemistry of tissue microarray sections, gene copy number analysis and tumor methylation specific PCR. Effects of CRBP-1 expression on proliferation/apoptosis gene array, protein and transcripts were investigatedin transfected A549 lung adenocarcinoma cells. Results: CRBP
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Genetic variants within the hTERT gene and the risk of colorectal cancer in Lynch syndrome

Genetic variants within the hTERT gene and the risk of colorectal cancer in Lynch syndrome ABSTRACT Lynch syndrome is an inherited cancer-predisposing disorder caused by germline mutations in the DNA mismatch repair (MMR) genes but there is a high degree of variability in cancer risk observed among carriers, suggesting the existence of modifying factors. Our aim was to investigate variants within the  hTERT  gene as a potential colorectal cancer (CRC) risk modifier for MMR gene mutation carriers. We identified 1098 MMR gene mutation carriers (420  MLH1 , 481  MSH2 , 126  MSH6 , 53  PMS2  and18  EPCAM ) from 330 families recruited from either family cancer clinics or population cancer registries of the Australasian Colorectal Cancer Family Registry between 1997 and 2012. Using weighted Cox regression after adjusting for ascertainment bias, we estimated associations between 23 SNPs within the  hTERT  gene and CRC risk. During 46,836 person-years observation, 392 (36%) carriers were diagn
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Mirk kinase inhibition targets ovarian cancer ascites

Mirk kinase inhibition targets ovarian cancer ascites ABSTRACT The Mirk/dyrk1B gene is commonly amplified or upregulated in ovarian cancers, and Mirk is an active kinase in these cancers. Mirk mediates cancer cell survival by decreasing toxic ROS levels through maintaining expression of a series of antioxidant genes, possibly through its transcriptional activator functions. Mirk has the unusual property of being most active in quiescent cancer cells because of marked transcriptional downregulation by Akt/mTOR signaling and by MEK/erk signaling in cycling cells. Metastatic ovarian cancer cells form ascites, non-adherent multicellular aggregates floating within the peritoneal fluid. Most ascites cancer cells are in a reversible quiescent, dormant state, suggesting that Mirk might be expressed in these quiescent cells and thus a therapeutic target. The current studies show that ovarian cancer cell line spheroids that mimic ascites cancer spheroids were largely quiescent in G0/G1, and enri
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The choice between p53-induced senescence and quiescence is determined in part by the mTOR pathway

The choice between p53-induced senescence and quiescence is determined in part by the mTOR pathway Abstract Transient induction of p53 can cause reversible quiescence and irreversible senescence. Using nutlin-3a (a small molecule that activates p53 without causing DNA damage), we have previously identified cell lines in which nutlin-3a caused quiescence. Importantly, nutlin-3a caused quiescence by actively suppressing the senescence program (while still causing cell cycle arrest). Noteworthy, in these cells nutlin-3a inhibited the mTOR (mammalian Target of Rapamycin) pathway, which is known to be involved in the senescence program. Here we showed that shRNA-mediated knockdown of TSC2, a negative regulator of mTOR, partially converted quiescence into senescence in these nutlin-arrested cells. In accord, in melanoma cell lines and mouse embryo fibroblasts, which easily undergo senescence in response to p53 activation, nutlin-3a failed to inhibit mTOR. In these senescence-prone cells, the
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Advances in Targeting Signal Transduction Pathways.

Advances in Targeting Signal Transduction Pathways. ABSTRACT Over the past few years, significant advances have occurred in both our understanding of the complexity of signal transduction pathways as well as the isolation of specific inhibitors which target key components in those pathways. Furthermore critical information is being accrued regarding how genetic mutations can affect the sensitivity of various types of patients to targeted therapy. Finally, genetic mechanisms responsible for the development of resistance after targeted therapy are being discovered which may allow the creation of alternative therapies to overcome resistance. This review will discuss some of the highlights over the past few years on the roles of key signaling pathways in various diseases, the targeting of signal transduction pathways and the genetic mechanisms governing sensitivity and resistance to targeted therapies. Mutations Alter the Activity of the Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways. The
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