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The rapid development of new anticancer drugs that are safe and effective is a common goal shared by basic scientists, clinicians and patients. The current review discusses one such agent, namely niclosamide, which has been used in the clinic for the treatment of intestinal parasite infections. Recent studies repeatedly identified niclosamide as a potential anticancer agent by various high-throughput screening campaigns. Niclosamide not only inhibits the Wnt/β-catenin, mTORC1, STAT3, NF-κB and Notch signaling pathways, but also targets mitochondria in cancer cells to induce cell cycle arrest, growth inhibition and apoptosis. A number of studies have established the anticancer activities of niclosamide in both in vitro and in vivo models. Moreover, the inhibitory effects of niclosamide on cancer stem cells provide further evidence for its consideration as a promising drug for cancer therapy. This article reviews various aspects of niclosamide as they relate to its efficacy against cancer and associated molecular mechanisms.

Read-through fusion transcripts that result from the splicing of two adjacent genes in the same coding orientation are a recently discovered type of chimeric RNA. We sought to determine if read-through fusion transcripts exist in breast cancer. We performed paired-end RNA-seq of 168 breast samples, including 28 breast cancer cell lines, 42 triple negative breast cancer primary tumors, 42 estrogen receptor positive (ER+) breast cancer primary tumors, and 56 non-malignant breast tissue samples. We analyzed the sequencing data to identify breast cancer associated read-through fusion transcripts. We discovered two recurrent read-through fusion transcripts that were identified in breast cancer cell lines, confirmed across breast cancer primary tumors, and were not detected in normal tissues (SCNN1A-TNFRSF1A and CTSD-IFITM10). Both fusion transcripts use canonical splice sites to join the last splice donor of the 5′ gene to the first splice acceptor of the 3′ gene, creating an in-frame fusion transcript. Western blots indicated that the fusion transcripts are translated into fusion proteins in breast cancer cells. Custom small interfering RNAs targeting the CTSD-IFITM10 fusion junction reduced expression of the fusion transcript and reduced breast cancer cell proliferation. Read-through fusion transcripts between adjacent genes with different biochemical functions represent a new type of recurrent molecular defect in breast cancer that warrant further investigation as potential biomarkers and therapeutic targets. Both breast cancer associated fusion transcripts identified in this study involve membrane proteins (SCNN1A-TNFRSF1A and CTSD-IFITM10), which raises the possibility that they could be breast cancer-specific cell surface markers.Electronic supplementary materialThe online version of this article (doi:10.1007/s10549-014-3019-2) contains supplementary material, which is available to authorized users.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor ␣ family of cytokines that preferentially induces apoptosis in transformed cells, making it a promising cancer therapy. However, many neoplasms are resistant to TRAIL-induced apoptosis by mechanisms that are poorly understood. We demonstrate that the expression of the small heat shock protein ␣B-crystallin (but not other heat shock proteins or apoptosis-regulating proteins) correlates with TRAIL resistance in a panel of human cancer cell lines. Stable expression of wild-type ␣B-crystallin, but not a pseudophosphorylation mutant impaired in its assembly and chaperone function, protects cancer cells from TRAIL-induced caspase-3 activation and apoptosis in vitro. Furthermore, selective inhibition of ␣B-crystallin expression by RNA interference sensitizes cancer cells to TRAIL. In addition, wild-type ␣B-crystallin promotes xenograft tumor growth and inhibits TRAIL-induced apoptosis in vivo in nude mice, whereas a pseudophosphorylation ␣B-crystallin mutant impaired in its anti-apoptotic function inhibits xenograft tumor growth. Collectively, these findings indicate that ␣B-crystallin is a novel regulator of TRAILinduced apoptosis and tumor growth. Moreover, these results demonstrate that targeted inhibition of ␣B-crystallin promotes TRAIL-induced apoptosis, thereby suggesting a novel strategy to overcome TRAIL resistance in cancer.Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), 1 also known as Apo2L, is a promising antitumor agent currently in preclinical studies that preferentially induces apoptosis in cancer cells, but not normal cells (1, 2). Like other members of the tumor necrosis factor family of cytokines, TRAIL is a type II transmembrane protein with an extracellular carboxyl terminus that mediates trimerization and receptor binding (3, 4). TRAIL plays a critical role in immune surveillance against tumors: TRAIL-deficient mice are more sensitive to chemical carcinogens and more susceptible to metastasis from mammary carcinoma xenografts (5). Recombinant soluble TRAIL induces apoptosis in many cancer cells in vitro and in vivo, and the native recombinant protein (amino acids 114 -281) appears to be quite tumor-selective (1, 6, 7). In addition, an antibody against one of the receptors of TRAIL (DR5) potently induces apoptosis in human hepatocellular carcinomas in vitro and in vivo, but not in normal human hepatocytes, thereby suggesting an additional therapeutic strategy to activate TRAIL apoptotic signaling (8). Although the mechanisms underlying the differential sensitivity of cancer and normal cells to TRAIL-induced apoptosis are poorly understood, the potential tumor selectivity of TRAIL distinguishes it from many other cancer therapies.TRAIL-induced apoptosis is mediated by the death-inducing signaling complex (DISC), which is composed of the TRAIL death receptors (DR4 and DR5), Fas-associated death domain (FADD), and the apical procaspases-8 and -10 (2). Trimeric TRAIL binds to its dea...

The ST6Gal-I sialyltransferase adds an α2–6-linked sialic acid to the N-glycans of certain receptors. ST6Gal-I mRNA has been reported to be upregulated in human cancer, but a prior lack of antibodies has limited immunochemical analysis of the ST6Gal-I protein. Here we show upregulated ST6Gal-I protein in several epithelial cancers, including many colon carcinomas. In normal colon, ST6Gal-I localized selectively to the base of crypts, where stem/progenitor cells are found, and the tissue staining patterns were similar to the established stem cell marker ALDH1. Similarly, ST6Gal-I expression was restricted to basal epidermal layers in skin, another stem/progenitor cell compartment. ST6Gal-I was highly expressed in induced pluripotent stem (iPS) cells, with no detectable expression in the fibroblasts from which iPS cells were derived. On the basis of these observations we investigated further an association of ST6Gal-I with cancer stem cells (CSCs). Selection of irinotecan resistance in colon carcinoma cells led to a greater proportion of CSCs compared with parental cells, as measured by the CSC markers CD133 and ALDH1 activity (Aldefluor). These chemoresistant cells exhibited a corresponding upregulation of ST6Gal-I expression. Conversely, shRNA-mediated attenuation of ST6Gal-I in colon carcinoma cells with elevated endogenous expression decreased the number of CD133/ALDH1-positive cells present in the cell population. Collectively, our results suggest that ST6Gal-I promotes tumorigenesis and may serve as a regulator of the stem cell phenotype in both normal and cancer cell populations.