The Y-box binding protein-1 (YB-1) transcription factor is associated with unfavorable clinical outcomes. However, the mechanisms underlying this association remain to be fully elucidated. We demonstrate that YB-1 phosphorylation, indicative of YB-1 activation, is a powerful marker of outcomes for ovarian cancer patients. In ovarian cancer, YB-1 phosphorylation is induced by activation of the lysophosphatidic acid (LPA) receptor (LPAR) via SRC-dependent transactivation of the epidermal growth factor receptor (EGFR) that is coupled to MAPK/p90 ribosomal S6 kinase (p90RSK), but not phosphatidylinositol 3-kinase (PI3K)/AKT signaling. Activation of the LPAR/SRC/EGFR/MAPK/p90RSK/YB-1 axis leads to production of the EGFR ligand amphiregulin (AREG). AREG induces ongoing YB-1 phosphorylation as well as YB-1-dependent AREG expression thus constituting an AREG/YB-1 self-reinforcing loop. Disruption of transactivation of the EGFR and the downstream self-reinforcing loop decreases invasiveness of ovarian cancer cells in vitro and limits ovarian cancer growth in xenograft models. These findings established the regulation and significance of YB-1 phosphorylation, therefore further exploration of this signaling axis as a therapeutic avenue in ovarian cancer is warranted.
We have previously reported that adenoviral vector-mediated interferon (IFN)-b gene therapy inhibits orthotopic growth of human prostate cancer cells in nude mice. The purpose of this study was to determine efficacy and mechanisms of this therapy in immunecompetent mice. TRAMP-C2Re3 mouse prostate cancer cells infected with 100 multiplicity of infection (MOI) Furthermore, quantitative reverse-transcriptional PCR analysis showed that AdmIFN-b therapy, in C57BL/6 but not the iNOS-null counterparts, reduced levels of the mRNAs for angiopoietin, basic fibroblast growth factor, matrix metalloproteinase-9, transforming growth factor-b1, vascular endothelial growth factor (VEGF)-A, and VEGF-B, as well as the antiapoptotic molecule endothelin-1. These data indicated that IFN-b gene therapy could be effective alternative for the treatment of locally advanced prostate cancer and suggest an obligatory role of NO in IFN-b antitumoral effects in vivo.
Background: Several distinct subtypes of breast cancer (Luminal, Basal-like and Her-2+) have been identified by gene expression profiling of breast cancers and cell lines. Although much is known about the regulation of cell signaling in each breast cancer subtype, little is known about subtype-specific energy metabolism and its regulation. The majority of cancers, including breast cancer, acquire an accelerated metabolic index as part of the transformation process. One of the most studied metabolic changes in cancer, referred to as the Warburg effect, is the increased uptake of glucose and its conversion to lactate; which is released from the cell, thus creating an astringent tumor microenvironment with high lactate and low pH. Accumulation of lactate in the tumor microenvironment presents cancer cells with a potential rich carbon source that could be exploited when the preferred nutrient sources, glucose and glutamine, are not abundant or available. Thus uptake and conversion of lactate to pyruvate and then entry into the TCA cycle and oxidative phosphorylation could generate energy that could potentially allow cancer cells to survive until other nutrients become available or until the cancer cells can invade and migrate toward nutrient rich environments, in other words, until they spread locally and metastasize. Methods and Results: Examination of 59 breast cancer cell lines shows differences in expression of numerous proteins and enzymes involved in cellular metabolism, including the lactate transporters (MCT), the enzyme lactate dehydrogenase (LDH), and glucose transporter proteins (GLUT). We found that MCT1 expression is lost in the Luminal subtype and correlates with loss of LDHB and the regulator and chaperone of MCT1, CD147 (Basigin). Conversely, MCT1 is highly expressed in Basal-like and normal cell lines, along with CD147 and LDHB. While monocarboxylate transporter proteins can transport bi-directionally, MCT1 preferentially transports lactate into the cell, while MCT4 transports lactate out of the cell. The loss of MCT1 in luminal cells suggests a distinct energy metabolism in this subtype versus basal-like cells. The basal-like subtype has been further categorized into Basal and Claudin-low subtypes. Claudin-low cells express stem-like markers such as CD44+/CD24-, EMT markers such as vimentin, and are low expressers of the Claudin proteins. We found that MCT1 and CD147 are highly expressed and differentially regulated in Claudin-low cell lines as compared to normal cells. We have evidence that high lactate (10mM) as a sole energy source delays ATP loss and apoptosis in MCT1 expressing cells, but not in luminal cell lines that lack MCT1. Thus, claudin-low tumors may benefit from local lactate production providing an unexpected energy source. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-05-03.
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