Schneider et al. Page 793

The phosphorylated sphingolipid metabolites sphingosine-1-phosphate (S1P) and ceramide-1-phosphate (C1P) are known to be highly bioactive and at physiologic concentrations may strongly enhance motility and adhesion in human rhabdomyosarcoma (RMS). Schneider and colleagues show that the bioactive effects of these metabolites are much stronger than the effects observed in response to known RMS prometastatic factors such as stromal derived factors-1 (SDF-1) or hepatocyte growth factor/scatter factor (HGF/SF). Moreover, the levels of S1P and C1P increased in several organs after γ-irradiation or chemotherapy, which indicates a treatment-specific induction of an unwanted prometastatic environment. Most importantly, the metastasis of RMS cells in response to S1P was effectively inhibited in vivo with the S1P-specific binder NOX-S93 that is based on a high-affinity Spiegelmer aptamer. Thus, bioactive lipids play a previously underappreciated role in the dissemination of RMS and the unwanted side effects of radio/chemotherapy by induction of a prometastatic microenvironment. Therefore, an antimetastatic treatment with S1P-specific scavenger activity, such as NOX-S93, could become a part of standard radio/chemotherapy.

Cui et al. Page 699

Taxane-based drugs such as docetaxel are frequently used as chemotherapy in cancer. Docetaxel-resistant lung adenocarcinoma (LAD) cells display chemoradiotherapy resistance and mesenchymal features with enhanced invasiveness and motility. Therefore, a better understanding of the nature of chemo- and radiotherapy resistance and the molecular mechanisms that govern chemotherapy-induced epithelial-to-mesenchymal transition (EMT) in LAD will lead to the identification of novel molecular targets. Cui and colleagues used in vitro and in vivo analyses to show that upregulation of the microRNA Let-7c could not only restore the chemo- or radiosensitivity but also promote the reversal of an EMT phenotype in the docetaxel-resistant LAD cells. In contrast, Let-7c inhibition decreased the chemo- or radiosensitivity of parental LAD cells. Additional study identified that Let-7c targets the prosurvival Bcl-2 family member, B-cell lymphoma–extra large (Bcl-xL), and that manipulation of Bcl-xL mimics the effects of altered Let-7c. Thus, Let-7c may emerge as an important biomarker for chemoradiotherapy response and metastasis as well as a potential therapeutic target for human LADs.

Kharbanda et al. Page 714

Therapy for estrogen receptor–positive (ER+) breast cancers with the antagonist tamoxifen is often associated with recurrent disease. Consequently, new targets are needed for the treatment of ER+ breast cancers that become resistant to tamoxifen. Kharbanda and colleagues show that the transmembrane mucin family member subunit MUC1-C oncoprotein confers tamoxifen resistance. Critically, targeting MUC1-C with a peptidomimetic was not only effective alone but was also effective in combination with tamoxifen in tamoxifen-resistant breast cancer cells. In the aggregate, these findings provide an experimental basis for the development of MUC1-C inhibitors for the treatment of breast cancer patients with tamoxifenresistant disease.

Jin et al. Page 736

MED1 is a component of the Mediator complex that bridges gene-specific factors to the basal transcriptional machinery. MED1 is known to be a critical coactivator for the androgen receptor (AR) and other transcription factors expressed in prostate epithelial cells. Jin and colleagues used immunohistochemistry (IHC) to show that MED1 is significantly overexpressed in human prostate cancer tissue and in an Nkx3.1:Pten-mutant mouse model of prostate cancer. Importantly, MED1 overexpression was correlated with elevated cellular proliferation. Further study using immunoblot and IHC assays revealed that hyperactivated ERK and/or PI3K/AKT signaling drive MED1 overexpression via direct phosphorylation. Moreover, ectopic MED1 overexpression in prostate cancer xenografts accelerates tumor growth, and through genomic analyses the expression of novel genes involved in inflammation, proliferation, and survival were altered. These results define MED1 as a key oncogenic target for ERK and PI3K/AKT signaling during prostate tumorigenesis, and as such, may represent a novel biomarker or target for therapeutic intervention.