Tumor cells activate autophagy in response to chemotherapyinduced DNA damage as a survival program to cope with metabolic stress. Here, we provide in vitro and in vivo evidence that histone deacetylase (HDAC)10 promotes autophagy-mediated survival in neuroblastoma cells. We show that both knockdown and inhibition of HDAC10 effectively disrupted autophagy associated with sensitization to cytotoxic drug treatment in a panel of highly malignant V-MYC myelocytomatosis viral-related oncogene, neuroblastoma derived-amplified neuroblastoma cell lines, in contrast to nontransformed cells. HDAC10 depletion in neuroblastoma cells interrupted autophagic flux and induced accumulation of autophagosomes, lysosomes, and a prominent substrate of the autophagic degradation pathway, p62/sequestosome 1. Enforced HDAC10 expression protected neuroblastoma cells against doxorubicin treatment through interaction with heat shock protein 70 family proteins, causing their deacetylation. Conversely, heat shock protein 70/heat shock cognate 70 was acetylated in HDAC10-depleted cells. HDAC10 expression levels in high-risk neuroblastomas correlated with autophagy in gene-set analysis and predicted treatment success in patients with advanced stage 4 neuroblastomas. Our results demonstrate that HDAC10 protects cancer cells from cytotoxic agents by mediating autophagy and identify this HDAC isozyme as a druggable regulator of advanced-stage tumor cell survival. Moreover, these results propose a promising way to considerably improve treatment response in the neuroblastoma patient subgroup with the poorest outcome.drug resistance | HDAC inhibitor | childhood tumors A utophagy is an evolutionarily highly conserved process that can be induced by metabolic or therapeutic stress, such as DNA damage-inducing drugs (1). The two dominant types of autophagy are macroautophagy and chaperone-mediated autophagy (CMA) (2). Macroautophagy is regulated by autophagyrelated genes (ATGs), including beclin-1 (ATG6) and microtubule-associated protein 1 light chain 3 (LC3) (ATG8), and involves the sequestration of cytoplasmic components within a double-membrane structure called the autophagosome and successive delivery to lysosomes for degradation (reviewed in ref.3). CMA targets specific cytosolic proteins to the lysosomes for protein degradation (4). During CMA, the cytosolic chaperone heat shock cognate (Hsc)70 binds proteins targeted for degradation and translocates them to the lysosomes (5), where they bind to the substrate protein receptor lysosome-associated membrane protein type 2A (LAMP-2A) (6).Inhibition of histone deacetylases (HDACs) by HDAC inhibitors (HDACis) have been shown to cause significant anti-tumor effects, including cell-cycle arrest, differentiation, and apoptosis, in a broad spectrum of hematologic and solid tumors (reviewed in ref. 7). The efficacy of HDACis are currently being evaluated for treating various cancers in clinical trials (7-9). Recent research carried out in several tumor cell lines has shown that apoptosis induced by HDACis i...
Defects in the apoptotic signaling cascades contribute to the poor therapeutic response of malignant gliomas. As glioblastomas are characterized by high expression levels of anti-apoptotic Bcl-2 family proteins, we studied the effects of the novel Bcl-2 inhibitor, ABT-737, on malignant glioma cells. ABT-737 treatment released the pro-apoptotic Bax protein from its binding partner Bcl-2 and potently induced apoptotic cell death in glioblastoma cells in vitro and in vivo. The local administration of ABT-737 prolonged the survival in an intracranial glioma xenograft model. Downregulation of Mcl-1 and overexpression of Bcl-2 sensitized the cells to ABT-737-mediated apoptosis. Moreover, ABT-737 potentiated the cytotoxicity of the chemotherapeutic drugs vincristine and etoposide, and of the death ligand TRAIL. As glioma stem cells may play a crucial role for the tumor progression and the resistance to treatment in glioblastomas, we investigated the effects of ABT-737 on the subpopulation of glioma cells exhibiting stem cell characteristics. Inhibition of proliferation and induction of apoptosis by ABT-737 were less efficient in glioma stem cells than in non-stem cell-like glioma cells. As the resistance of glioma stem cells was associated with high Mcl-1 expression levels, ABT-737 treatment combined with downregulation of Mcl-1 could represent a promising novel approach in glioblastoma treatment.
Compared to systematic, transperineal biopsy as a reference test, magnetic resonance imaging targeted biopsy alone detected as many Gleason score 7 or greater tumors while simultaneously mitigating the detection of lower grade disease. The gold standard for cancer detection in primary biopsy is a combination of systematic and targeted cores.
contributed equally to the present study.
Objectives• To define terms and processes and agree on a minimum dataset in relation to transperineal prostate biopsy procedures and enhanced prostate diagnostics.• To identify the need for further evaluation and establish a collaborative research practice.
Patients and Methods• A 19-member multidisciplinary panel rated 66 items for their appropriateness and their definition to be incorporated into the international databank using the Research and Development/University of California Los Angeles Appropriateness Method. • The item list was developed from interviews conducted with healthcare professionals from urology, radiology, pathology and engineering.
Results• The panel agreed on 56 items that were appropriate to be incorporated into a prospective database.• In total, 10 items were uncertain and were omitted. These items were within the categories: definitions (n = 2), imaging (n = 1), surgical protocols (n = 2) and histology (n = 5).
Conclusions• The components of a minimum dataset for transperineal prostate biopsy have been defined. • This provides an opportunity for multicentre collaborative data analysis and technique development.• The findings of the present study will facilitate prospective studies into the application and outcome of transperineal prostate biopsies.
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