4 results on '"Altamirano-Dimas, M."'
Search Results
2. Up-Regulated Expression of LAMP2 and Autophagy Activity during Neuroendocrine Differentiation of Prostate Cancer LNCaP Cells.
- Author
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Morell C, Bort A, Vara-Ciruelos D, Ramos-Torres Á, Altamirano-Dimas M, Díaz-Laviada I, and Rodríguez-Henche N
- Subjects
- Blotting, Western, Cell Line, Tumor, Cell Transformation, Neoplastic metabolism, Gene Expression Regulation, Neoplastic physiology, Humans, Lysosomal-Associated Membrane Protein 2 physiology, Male, Microscopy, Confocal, Oligonucleotide Array Sequence Analysis, Prostatic Neoplasms physiopathology, Real-Time Polymerase Chain Reaction, Transcriptome, Up-Regulation, Autophagy physiology, Lysosomal-Associated Membrane Protein 2 metabolism, Prostatic Neoplasms metabolism
- Abstract
Neuroendocrine (NE) prostate cancer (PCa) is a highly aggressive subtype of prostate cancer associated with resistance to androgen ablation therapy. In this study, we used LNCaP prostate cancer cells cultured in a serum-free medium for 6 days as a NE model of prostate cancer. Serum deprivation increased the expression of NE markers such as neuron-specific enolase (NSE) and βIII tubulin (βIII tub) and decreased the expression of the androgen receptor protein in LNCaP cells. Using cDNA microarrays, we compared gene expression profiles of NE cells and non-differentiated LNCaP cells. We identified up-regulation of 155 genes, among them LAMP2, a lysosomal membrane protein involved in lysosomal stability and autophagy. We then confirmed up-regulation of LAMP2 in NE cells by qRT-PCR, Western blot and confocal microscopy assays, showing that mRNA up-regulation correlated with increased levels of LAMP2 protein. Subsequently, we determined autophagy activity in NE cells by assessing the protein levels of SQSTM/p62 and LC3 by Western blot and LC3 and Atg5 mRNAs content by qRT-PCR. The decreased levels of SQSTM/p62 was accompanied by an enhanced expression of LC3 and ATG5, suggesting activation of autophagy in NE cells. Blockage of autophagy with 1μM AKT inhibitor IV, or by silencing Beclin 1 and Atg5, prevented NE cell differentiation, as revealed by decreased levels of the NE markers. In addition, AKT inhibitor IV as well as Beclin1 and Atg5 kwockdown attenuated LAMP2 expression in NE cells. On the other hand, LAMP2 knockdown by siRNA led to a marked blockage of autophagy, prevention of NE differentiation and decrease of cell survival. Taken together, these results suggest that LAMP2 overexpression assists NE differentiation of LNCaP cells induced by serum deprivation and facilitates autophagy activity in order to attain the NE phenotype and cell survival. LAMP2 could thus be a potential biomarker and potential target for NE prostate cancer., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2016
- Full Text
- View/download PDF
3. Not all NOTCH Is Created Equal: The Oncogenic Role of NOTCH2 in Bladder Cancer and Its Implications for Targeted Therapy.
- Author
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Hayashi T, Gust KM, Wyatt AW, Goriki A, Jäger W, Awrey S, Li N, Oo HZ, Altamirano-Dimas M, Buttyan R, Fazli L, Matsubara A, and Black PC
- Subjects
- Animals, Cell Line, Tumor, Cell Proliferation genetics, Enzyme Activation genetics, Gene Dosage genetics, Humans, Lymphatic Metastasis genetics, Mice, Neoplasm Invasiveness genetics, RNA Interference, RNA, Small Interfering genetics, Receptor, Notch1 biosynthesis, Receptor, Notch2 antagonists & inhibitors, Receptor, Notch3 biosynthesis, Signal Transduction genetics, Xenograft Model Antitumor Assays, Epithelial-Mesenchymal Transition genetics, Receptor, Notch2 genetics, Receptor, Notch2 metabolism, Urinary Bladder Neoplasms pathology
- Abstract
Purpose: Recent molecular analyses of bladder cancer open the door to significant advances in targeted therapies. NOTCH has been identified as a tumor suppressor in bladder cancer, but prior reports have focused on NOTCH1 Here we hypothesized that NOTCH2 is an oncogene suitable for therapeutic targeting in bladder cancer., Experimental Design: We studied genomic aberrations of NOTCH, compared survival and tumor progression according to NOTCH2 expression levels, and studied NOTCH2 function in vitro and vivo, Results: We report a high rate of NOTCH2 copy number gain in bladder cancer. High NOTCH2 expression was identified especially in the basal subtype and in mesenchymal tumors. NOTCH2 activation correlated with adverse disease parameters and worse prognosis by immunohistochemistry. Forced overexpression of the intracellular domain of NOTCH2 (N2ICD) induced cell growth and invasion by cell-cycle progression, maintenance of stemness and epithelial-to-mesenchymal transition (EMT). These effects were abrogated by silencing of CSL, indicating that the effects were mediated through the canonical NOTCH signaling pathway. In an orthotopic xenograft model, forced overexpression of N2ICD increased growth, invasion, and metastasis. To explore the potential for therapeutic targeting of NOTCH2, we first silenced the receptor with shRNA and subsequently treated with a specific inhibitory antibody. Both interventions decreased cell growth, invasion, and metastasis in vitro and in the orthotopic xenograft model., Conclusions: We have demonstrated that NOTCH2 acts as an oncogene that promotes bladder cancer growth and metastasis through EMT, cell-cycle progression, and maintenance of stemness. Inhibition of NOTCH2 is a rational novel treatment strategy for invasive bladder cancer. Clin Cancer Res; 22(12); 2981-92. ©2016 AACR., (©2016 American Association for Cancer Research.)
- Published
- 2016
- Full Text
- View/download PDF
4. The retinoblastoma protein regulates hypoxia-inducible genetic programs, tumor cell invasiveness and neuroendocrine differentiation in prostate cancer cells.
- Author
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Labrecque MP, Takhar MK, Nason R, Santacruz S, Tam KJ, Massah S, Haegert A, Bell RH, Altamirano-Dimas M, Collins CC, Lee FJ, Prefontaine GG, Cox ME, and Beischlag TV
- Subjects
- Apoptosis, Cell Movement, Cell Proliferation, Gene Expression Profiling, Gene Regulatory Networks, Humans, Male, Neoplasm Invasiveness, Neuroendocrine Cells metabolism, Prostatic Neoplasms metabolism, Retinoblastoma Protein genetics, Tumor Cells, Cultured, Biomarkers, Tumor genetics, Cell Differentiation, Hypoxia genetics, Neuroendocrine Cells pathology, Prostatic Neoplasms genetics, Prostatic Neoplasms pathology, Retinoblastoma Protein metabolism
- Abstract
Loss of tumor suppressor proteins, such as the retinoblastoma protein (Rb), results in tumor progression and metastasis. Metastasis is facilitated by low oxygen availability within the tumor that is detected by hypoxia inducible factors (HIFs). The HIF1 complex, HIF1α and dimerization partner the aryl hydrocarbon receptor nuclear translocator (ARNT), is the master regulator of the hypoxic response. Previously, we demonstrated that Rb represses the transcriptional response to hypoxia by virtue of its association with HIF1. In this report, we further characterized the role Rb plays in mediating hypoxia-regulated genetic programs by stably ablating Rb expression with retrovirally-introduced short hairpin RNA in LNCaP and 22Rv1 human prostate cancer cells. DNA microarray analysis revealed that loss of Rb in conjunction with hypoxia leads to aberrant expression of hypoxia-regulated genetic programs that increase cell invasion and promote neuroendocrine differentiation. For the first time, we have established a direct link between hypoxic tumor environments, Rb inactivation and progression to late stage metastatic neuroendocrine prostate cancer. Understanding the molecular pathways responsible for progression of benign prostate tumors to metastasized and lethal forms will aid in the development of more effective prostate cancer therapies., Competing Interests: The authors have no conflicts of interest to report.
- Published
- 2016
- Full Text
- View/download PDF
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