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Showing posts from June, 2020

Autoantibodies against oncogenic ERG protein in prostate cancer: potential use in diagnosis and prognosis in a panel with C-MYC, AMACR and HERV-K Gag

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Autoantibodies against oncogenic ERG protein in prostate cancer: potential use in diagnosis and prognosis in a panel with C-MYC, AMACR and HERV-K Gag ABSTRACT Overdiagnosis and overtreatment of prostate cancer (CaP) is attributable to widespread reliance on PSA screening in the US. This has prompted us and others to search for improved biomarkers for CaP, to facilitate early detection and disease stratification. In this regard, autoantibodies (AAbs) against tumor antigens could serve as potential candidates for diagnosis and prognosis of CaP. Towards this, our goals were: i) To investigate whether AAbs against ERG oncoprotein (overexpressed in 25-50% of Caucasian American and African American CaP) are present in the sera of CaP patients; ii) To evaluate an AAb panel to enhance CaP detection. The resul­­ts using an enzyme-linked immunosorbent assay (ELISA) showed that anti-ERG AAbs are present in a significantly higher proportion in the sera of CaP patients compared to healthy controls

Methylation of CHFR sensitizes esophageal squamous cell cancer to docetaxel and paclitaxel

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Methylation of CHFR sensitizes esophageal squamous cell cancer to docetaxel and paclitaxel ABSTRACT Esophageal squamous cell carcinoma (ESCC) is one of the most common malignancies worldwide. Both genetic and epigenetic changes are involved in esophageal carcinogenesis. CHFR methylation has been found frequently in different cancers and is regarded as a marker of taxane sensitivity. CHFR methylation was found in 0% (0/16) of normal mucosa, 2.9% (1/34) of grade I dysplasia, 0% (0/8) of grade II dysplasia, 12.5% (1/8) of grade III dysplasia and 45% (49/109) of invasive cancer. When treated with docetaxel or paclitaxel, cell viability was lower in CHFR methylated esophageal cancer cells than in unmethylated cells (p<0.05). No difference was found with either cisplatin or VP16 treatment in either group (p>0.05). In CHFR methylated cells, treatment with docetaxel or paclitaxel resulted in almost all cells being suspended in G0/G1 phase of the cell cycle. After 5-AZ treatment, there wa

Multiple myeloma cell lines and primary tumors proteome: protein biosynthesis and Immune system as potential therapeutic targets

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Multiple myeloma cell lines and primary tumors proteome: protein biosynthesis and Immune system as potential therapeutic targets ABSTRACT Despite great advance in multiple myeloma (MM) treatment since 2000s, it is still an incurable disease and novel therapies are welcome. Therefore, the purpose of this study was to explore MM plasma cells’ (MM-PC) proteome, in comparison with their normal counterparts (derived from palatine tonsils of normal donors, ND-PC), in order to find potential therapeutic targets expressed on the surface of these cells. We also aimed to evaluate the proteome of MM cell lines with different genetic alterations, to confirm findings obtained with primary tumor cells. Bone marrow (BM) samples from eight new cases of MM and palatine tonsils from seven unmatched controls were submitted to PC separation and, in addition to two MM cell lines (U266, RPMI-8226), were submitted to protein extraction for mass spectrometry analyses. A total of 81 proteins were differentiall

Combinations of genetic data in a study of oral cancer

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Combinations of genetic data in a study of oral cancer ABSTRACT In the single locus strategy a number of genetic variants are analyzed, in order to find variants that are distributed significantly different between controls and patients. A supplementary strategy is to analyze combinations of genetic variants. A combination that is the genetic basis for a polygenic disorder will not occur in in control persons genetically unrelated to patients, so the strategy is to analyze combinations of genetic variants present exclusively in patients. In a previous study of oral cancer and leukoplakia 325 SNPs were analyzed. This study has been supplemented with an analysis of combinations of two SNP genotypes from among the 325 SNPs. Two clusters of combinations containing 95 patient specific combinations were significantly associated with oral cancer or leukoplakia. Of 373 patients with oral cancer 205 patients had a number of these 95 combinations in their genome, whereas none of 535 control pers

PTEN deficiency and mutant p53 confer glucose-addiction to thyroid cancer cells: impact of glucose depletion on cell proliferation, cell survival, autophagy and cell migration

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PTEN deficiency and mutant p53 confer glucose-addiction to thyroid cancer cells: impact of glucose depletion on cell proliferation, cell survival, autophagy and cell migration ABSTRACT Proliferating cancer cells oxidize glucose through the glycolytic pathway. Since this metabolism is less profitable in terms of ATP production, cancer cells consume large quantity of glucose, and those that experience insufficient blood supply become glucose-addicted. We have analyzed the response to glucose depletion in WRO and FTC133 follicular thyroid cancer cells, which differ in the expression of two key regulators of the glucose metabolism. WRO cells, which express wild type p53 and PTEN, showed a higher rate of cell proliferation and were much less sensitive to glucose-depletion than FTC133 cells, which are PTEN null and express mutant p53. Glucose depletion slowed-down the autophagy flux in FTC133 cells, not in WRO cells. In a wound-healing assay, WRO cells were shown to migrate faster than FTC13

Identification of a novel lytic peptide for the treatment of solid tumours

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Identification of a novel lytic peptide for the treatment of solid tumours ABSTRACT Originally known as host defence peptides for their substantial bacteriotoxic effects, many cationic antimicrobial peptides also exhibit a potent cytotoxic activity against cancer cells. Their mode of action is characterized mostly by electrostatic interactions with the plasma membrane, leading to membrane disruption and rapid necrotic cell death. In this work, we have designed a novel cationic peptide of 27 amino acids (Cypep-1), which shows efficacy against a number of cancer cell types, both  in vitro  and  in vivo , while normal human fibroblasts were significantly less affected. Surface plasmon resonance experiments as well as liposome leakage assays monitored by fluorescence spectroscopy revealed a substantial binding affinity of Cypep-1 to negatively charged liposomes and induced significant leakage of liposome content after exposure to the peptide. The observed membranolytic effect of Cypep-1 wa

Internal ribosome entry site of bFGF is the target of thalidomide for IMiDs development in multiple myeloma

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Internal ribosome entry site of bFGF is the target of thalidomide for IMiDs development in multiple myeloma ABSTRACT Although new analogues of immunomodulatory drugs (IMiDs) are being developed for MM, the molecular mechanism of these drugs remains unclear. In the current study, we used MM cell lines as a model to investigate the molecular mechanism of thalidomide and to compare its potency with IMiDs such as pomalidomide. We determined that thalidomide did not inhibit cell proliferation of RPMI8226 and U266 MM cells, whereas pomalidomide showed a significant inhibitory effect on these two MM cell lines. Interestingly, we further demonstrated that although thalidomide down-regulated bFGF translation through the inhibition of IRES even at 0.1 µg/ml, pomalidomide did not have a similar affect bFGF levels. A colony formation assay demonstrated that thalidomide and the bFGF knock-down clones caused a significant reduction in the clonogenic ability of MM cells, and treatment with exogenous

The normal function of the cancer kinase Mirk/dyrk1B is to reduce reactive oxygen species

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The normal function of the cancer kinase Mirk/dyrk1B is to reduce reactive oxygen species ABSTRACT Mirk kinase is a gene upregulated and sometimes amplified in pancreatic cancers and in ovarian cancers, but expressed at very low levels in most normal diploid cells except for skeletal muscle. The muscle cell function of Mirk kinase selected for by cancer cells is unknown. It is now shown that Mirk protein is expressed at low levels and is largely nuclear in cycling skeletal muscle C2C12 myoblasts, but is translocated to the cytoplasm and upregulated when myoblasts initiate differentiation, as shown by immunofluorescence staining and by cell fractionation. Either Mirk depletion or Mirk kinase inhibition increased ROS levels in cycling C2C12 myoblasts. However, Mirk protein is localized in the cytoplasm of mature muscle fibers, specifically in the fast twitch fibers of human skeletal muscle where toxic ROS levels are generated by muscle contraction. C2C12 myoblasts at high density in diff

Generation of a mouse model of T-cell lymphoma based on chronic LPS challenge and TGF-β signaling disruption

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Generation of a mouse model of T-cell lymphoma based on chronic LPS challenge and TGF-β signaling disruption ABSTRACT Alcoholic liver disease has various manifestations: asymptomatic steatosis, alcoholic hepatitis and alcoholic cirrhosis, conditions that substantially increase the risk for developing hepatocellular carcinoma(HCC). The Transforming Growth Factor-β (TGF-β) signaling pathway is a major regulator in chronic liver diseases contributing to liver disease progression from liver injury, inflammation and fibrosis to HCC. With the aim of generating a mouse model of alcoholic liver disease that would rapidly develop steatosis, inflammation as well as fibrosis, we formulated a regimen that combined chronic injections of low dose (2mg/kg) lipopolysaccharide (LPS) with Lieber DeCarli-based diet containing 6.7% ethanol feeding to mice with impaired TGF-β signaling through constitutive disruption of β2-spectrin and/or Smad3. Unexpectedly, the mice treated with chronic low dose LPS and

STAT activation status differentiates leukemogenic from non-leukemogenic stem cells in AML and is suppressed by arsenic in t(6;9)-positive AML

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STAT activation status differentiates leukemogenic from non-leukemogenic stem cells in AML and is suppressed by arsenic in t(6;9)-positive AML A BSTRACT Acute myeloid leukemia (AML) is characterized by an aberrant self-renewal of hematopoietic stem cells (HSC) and a block in differentiation. The major therapeutic challenge is the characterization of the leukemic stem cell as a target for the eradication of the disease. Until now the biology of AML-associated fusion proteins (AAFPs), such as the t(15;17)-PML/RARα, t(8;21)-RUNX1/RUNX1T1 and t(6;9)-DEK/NUP214, all able to induce AML in mice, was investigated in different models and genetic backgrounds, not directly comparable to each other. To avoid the bias of different techniques and models we expressed these three AML-inducing oncogenes in an identical genetic background and compared their influence on the HSC compartment  in vitro  and  in vivo . These AAFPs exerted differential effects on HSCs and PML/RARα, similar to DEK/NUP214, ind

Origins of cancer: tackling provocative questions

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Origins of cancer: tackling provocative questions ABSTRACT Despite the tremendous progress that scientists have made throughout the history of cancer research, there are still far too many deaths and remaining scientific questions for us to be content with our current knowledge of the disease. The eighth Origins of Cancer symposium, held July 21, 2017 at Van Andel Research Institute, was organized around the theme of “Tackling Provocative Questions” to stimulate discussion of several of these unresolved paradoxes in the field of cancer research. The symposium highlighted recent progress from the National Cancer Institute’s Provocative Questions Initiative, a program that offers research support to scientists who propose innovative strategies to address one of the featured questions. Accordingly, each of our eight distinguished speakers had received funding through this Initiative or performs research that closely aligns with one of these important yet understudied questions. From micro