Select Bcl-2 antagonism restores chemotherapy sensitivity in high-risk neuroblastoma.

Background: Pediatric patients with high-risk neuroblastoma (HR NB) often fail to respond to upfront intensive multimodal therapy. Tumor-acquired suppression of apoptosis contributes to therapy resistance. Many HR NB tumors depend on the anti-apoptotic protein Bcl-2 for survival, through Bcl-2 sequestration and inhibition of the pro-apoptotic protein, Bim.

TIMP-1 Inhibits Apoptosis in Lung Adenocarcinoma Cells via Interaction with Bcl-2.

Tissue inhibitors of metalloproteinases (TIMPs) are multifaceted molecules that exhibit properties beyond their classical proteinase inhibitory function. Although TIMP-1 is a known inhibitor of apoptosis in mammalian cells, the mechanisms by which it exerts its effects are not well-established. Our earlier studies using H2009 lung adenocarcinoma cells, implanted in the CNS, showed that TIMP-1 overexpressing H2009 cells (HB-1), resulted in more aggressive tumor kinetics and increased vasculature.

EGFR signaling defines Mcl⁻1 survival dependency in neuroblastoma.

The pediatric solid tumor neuroblastoma (NB) often depends on the anti-apoptotic protein, Mcl(-)1, for survival through Mcl(-)1 sequestration of pro-apoptotic Bim. High affinity Mcl(-)1 inhibitors currently do not exist such that novel methods to inhibit Mcl(-)1 clinically are in high demand. Receptor tyrosine kinases (RTK) regulate Mcl(-)1 in many cancers and play a role in NB survival, yet how they regulate Bcl(-)2 family interactions in NB is unknown.

Metabolomic profiling reveals potential markers and bioprocesses altered in bladder cancer progression.

Although alterations in xenobiotic metabolism are considered causal in the development of bladder cancer, the precise mechanisms involved are poorly understood. In this study, we used high-throughput mass spectrometry to measure over 2,000 compounds in 58 clinical specimens, identifying 35 metabolites which exhibited significant changes in bladder cancer. This metabolic signature distinguished both normal and benign bladder from bladder cancer.

Metabolomic profiling reveals a role for androgen in activating amino acid metabolism and methylation in prostate cancer cells.

Prostate cancer is the second leading cause of cancer related death in American men. Development and progression of clinically localized prostate cancer is highly dependent on androgen signaling. Metastatic tumors are initially responsive to anti-androgen therapy, however become resistant to this regimen upon progression.

Targeting levels or oligomerization of nucleophosmin 1 induces differentiation and loss of survival of human AML cells with mutant NPM1.

Nucleophosmin 1 (NPM1) is an oligomeric, nucleolar phosphoprotein that functions as a molecular chaperone for both proteins and nucleic acids. NPM1 is mutated in approximately one-third of patients with AML. The mutant NPM1c+ contains a 4-base insert that results in extra C-terminal residues encoding a nuclear export signal, which causes NPM1c+ to be localized in the cytoplasm.

Heat shock protein 90 inhibition depletes TrkA levels and signaling in human acute leukemia cells.

Nerve growth factor (NGF) induces autophosphorylation and downstream progrowth and prosurvival signaling from the receptor tyrosine kinase TrkA. Overexpression or activating mutation of TrkA has been described in human acute myeloid leukemia cells. In the present study, we show the chaperone association of TrkA with heat shock protein 90 (hsp90) and the inhibitory effect of the hsp90 inhibitor, 17-DMAG, on TrkA levels and signaling in cultured and primary myeloid leukemia cells.

Role of CAAT/enhancer binding protein homologous protein in panobinostat-mediated potentiation of bortezomib-induced lethal endoplasmic reticulum stress in mantle cell lymphoma cells.

Purpose: Bortezomib induces unfolded protein response (UPR) and endoplasmic reticulum stress, as well as exhibits clinical activity in patients with relapsed and refractory mantle cell lymphoma (MCL). Here, we determined the molecular basis of the improved in vitro and in vivo activity of the combination of the pan-histone deacetylase inhibitor panobinostat and bortezomib against human, cultured, and primary MCL cells.

Experimental Design: Immunoblot analyses, reverse transcription-PCR, and immunofluorescent and electron microscopy were used to determine the effects of panobinostat on bortezomib-induced aggresome formation and endoplasmic reticulum stress in MCL cells.

Treatment with panobinostat induces glucose-regulated protein 78 acetylation and endoplasmic reticulum stress in breast cancer cells.

Increased levels of misfolded polypeptides in the endoplasmic reticulum (ER) triggers the dissociation of glucose-regulated protein 78 (GRP78) from the three transmembrane ER-stress mediators, i.e., protein kinase RNA-like ER kinase (PERK), activating transcription factor-6 (ATF6), and inositol-requiring enzyme 1alpha, which results in the adaptive unfolded protein response (UPR).

Molecular detection of B-cell neoplasms by specific DNA methylation biomarkers.

A novel, easy to perform PCR-based method employing specific DNA methylation biomarkers to detect B-cell neoplasms in a variety of B-cell lines and B lymphoblastic leukemia (B-ALL) patient specimens has been developed. This method detects as few as 5 B-ALL cells, or 1 B-ALL cell in 1,000,000 normal background blood cells using a single marker, DLC-1 gene CpG island (CGI) methylation. By adding two additional markers PCDHGA12 and RPIB9, over 80% of B-ALL cases were detected in patients' bone marrow and/or peripheral blood specimens.