Explore the vast range of titles available.

ObjectiveIncreased de novo fatty acid (FA) synthesis and cholesterol biosynthesis have been independently described in many tumour types, including hepatocellular carcinoma (HCC).DesignWe investigated the functional contribution of fatty acid synthase (Fasn)-mediated de novo FA synthesis in a murine HCC model induced by loss of Pten and overexpression of c-Met (sgPten/c-Met) using liver-specific Fasn knockout mice. Expression arrays and lipidomic analysis were performed to characterise the global gene expression and lipid profiles, respectively, of sgPten/c-Met HCC from wild-type and Fasn knockout mice. Human HCC cell lines were used for in vitro studies.ResultsAblation of Fasn significantly delayed sgPten/c-Met-driven hepatocarcinogenesis in mice. However, eventually, HCC emerged in Fasn knockout mice. Comparative genomic and lipidomic analyses revealed the upregulation of genes involved in cholesterol biosynthesis, as well as decreased triglyceride levels and increased cholesterol esters, in HCC from these mice. Mechanistically, loss of Fasn promoted nuclear localisation and activation of sterol regulatory element binding protein 2 (Srebp2), which triggered cholesterogenesis. Blocking cholesterol synthesis via the dominant negative form of Srebp2 (dnSrebp2) completely prevented sgPten/c-Met-driven hepatocarcinogenesis in Fasn knockout mice. Similarly, silencing of FASN resulted in increased SREBP2 activation and hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase (HMGCR) expression in human HCC cell lines. Concomitant inhibition of FASN-mediated FA synthesis and HMGCR-driven cholesterol production was highly detrimental for HCC cell growth in culture.ConclusionOur study uncovers a novel functional crosstalk between aberrant lipogenesis and cholesterol biosynthesis pathways in hepatocarcinogenesis, whose concomitant inhibition might represent a therapeutic option for HCC.

Previous data indicate that Tankyrase inhibitors exert anti-growth functions in many cancer cell lines due to their ability to inactivate the YAP protooncogene. In the present manuscript, we investigated the effect of Tankyrase inhibitors on the growth of hepatocellular carcinoma (HCC) cell lines and the molecular mechanisms involved. For this purpose, we performed cell proliferation assay by colony-forming ability in seven human HCC cells subjected to XAV-939 and G007-LK Tankyrase inhibitors. Noticeably, the two Tankyrase inhibitors suppressed the HCC cell growth in a dose-dependent manner. Furthermore, we found that Tankyrase inhibitors synergized with MEK and AKT inhibitors to suppress HCC cell proliferation. At the molecular level, Tankyrase inhibitors significantly decreased YAP protein levels, reduced the expression of YAP target genes, and inhibited YAP/TEAD luciferase reporter activity. In addition, Tankyrase inhibitors administration was accompanied by upregulation of Angiomotin-like 1 (AMOTL1) and Angiomotin-like 2 (AMOTL2) proteins, two major negative regulators of YAP. Altogether, the present data indicate that XAV-939 and G007-LK Tankyrase inhibitors could suppress proliferation of hepatocellular carcinoma cells and downregulate YAP/TAZ by stabilizing AMOTL1 and AMOTL2 proteins, thus representing new potential anticancer drugs against hepatocellular carcinoma.

Interferon-induced transmembrane protein 3 (IFITM3) is an important anti-virus protein and has been recently shown to play a role in human cancer development. Thus, the present study aimed to assess the expression of the IFITM3 protein in breast cancer tissues and to investigate the in vitro effects of IFITM3 knockdown in the regulation of breast cancer cell growth and cell cycle distributions. A total of 64 patients of breast cancer and the matched normal tissue specimens were obtained for immunohistochemical analysis of IFITM3 expression. Lentivirus-carrying IFITM3 shRNA was used to knock down IFITM3 expression in breast cancer cell lines. Phenotypic changes of cell viability, growth, colony formation and cell cycle distribution was also assayed using flow cytometry, MTT, BrdU incorporation and colony formation assays. The IFITM3 protein was highly expressed in invasive breast cancer compared to normal tissues and was significantly associated with estrogen receptor and progesterone receptor status. The lentivirus-carried IFITM3 shRNA significantly reduced the expression of IFITM3 mRNA and protein in breast cancer cells, inhibiting tumor cell viability, growth and colony formation, arrested tumor cells at the G0/G1 phase of the cell cycle and reduced the number of cells in the S phase of the cell cycle. Expression of IFITM3 protein could be a potential therapeutic target in future treatment of breast cancer.

Cancerous inhibitor of protein phosphatase 2A (CIP2A) is a recently identified human oncoprotein that can stabilize some proteins by inhibiting degradation mediated by protein phosphatase 2A (PP2A), and its level in cancer is associated with resistance to chemotherapy. However, whether CIP2A could increase chemoresistance of prostate cancer (PCa) cells to chemotherapeutic agent cabazitaxel remains unclear. To determine whether CIP2A serves as a potential therapeutic target of human PCa, we utilized small interference RNA (siRNA) to knock down CIP2A expression in human PCa cells and analyzed their phenotypic changes. The data demonstrated that CIP2A was significantly elevated in mCRPC cell lines C4-2 and ARCaP(M) at both the mRNA and protein levels. CIP2A silencing led to decreased proliferation and enhanced chemosensitivity and apoptosis to cabazitaxel in human PCa cells, as well as reduced Akt phosphorylation. Our data suggesting critical roles of CIP2A in PCa cells chemoresistance to cabazitaxel and raising the possibility of CIP2A inhibition as a promising approach for chemosensitization of metastatic castration-resistant prostate cancer (mCRPC).

Hepatocellular carcinoma (HCC) is a deadly form of liver malignancy with limited treatment options. Amplification and/or overexpression of c-MYC is one of the most frequent genetic events in human HCC. The mammalian target of Rapamycin Complex 1 (mTORC1) is a major functional axis regulating various aspects of cellular growth and metabolism. Recently, we demonstrated that mTORC1 is necessary for c-Myc driven hepatocarcinogenesis as well as for HCC cell growth in vitro. Among the pivotal downstream effectors of mTORC1, upregulation of Fatty Acid Synthase (FASN) and its mediated de novo lipogenesis is a hallmark of human HCC. Here, we investigated the importance of FASN on c-Myc-dependent hepatocarcinogenesis using in vitro and in vivo approaches. In mouse and human HCC cells, we found that FASN suppression by either gene silencing or soluble inhibitors more effectively suppressed proliferation and induced apoptosis in the presence of high c-MYC expression. In c-Myc/Myeloid cell leukemia 1 (MCL1) mouse liver tumor lesions, FASN expression was markedly upregulated. Most importantly, genetic ablation of Fasn profoundly delayed (without abolishing) c-Myc/MCL1 induced HCC formation. Liver tumors developing in c-Myc/MCL1 mice depleted of Fasn showed a reduction in proliferation and an increase in apoptosis when compared with corresponding lesions from c-Myc/MCL1 mice with an intact Fasn gene. In human HCC samples, a significant correlation between the levels of c-MYC transcriptional activity and the expression of FASN mRNA was detected. Altogether, our study indicates that FASN is an important effector downstream of mTORC1 in c-MYC induced HCC. Targeting FASN may be helpful for the treatment of human HCC, at least in the tumor subset displaying c-MYC amplification or activation.

Breast cancer is a major cause of cancer-related death among women. Tumor protein D52-like 2 (TPD52L2) is one member of the TPD52 family, which has been shown to function in mediating cell proliferation, apoptosis, and vehicle trafficking. TPD52 was originally identified in human breast carcinoma. In this study, the authors found that TPD52L2 is extensively expressed in multiple human breast cancer cell lines. To elucidate the functional role of TPD52L2 in breast cancer, the authors employed lentivirus-mediated short hairpin RNA (shRNA) to knock down TPD52L2 in one breast cancer cell line, ZR-75-30, which showed high TPD52L2 expression. The shRNA-mediated TPD52L2 knockdown inhibited the proliferation and colony formation in ZR-75-30 cells, as determined by MTT and colony formation assays. Knockdown of TPD52L2 led to an accumulation of cells in the G0/G1 phase of the cell cycle. Furthermore, knockdown of TPD52L2 promoted GSK3β phosphorylation in ZR-75-30 cells. This investigation indicates that TPD52L2 plays an essential role in the growth of breast cancer cells, which may contribute to provide gene therapy for breast cancer treatment.

Cancerous inhibitor of protein phosphatase 2A (CIP2A) is a recently identified human oncoprotein that can stabilize some proteins by inhibiting degradation mediated by protein phosphatase 2A (PP2A), and its level in cancer is associated with resistance to chemotherapy. However, whether CIP2A could increase chemoresistance of prostate cancer (PCa) cells to chemotherapeutic agent cabazitaxel remains unclear. To determine whether CIP2A serves as a potential therapeutic target of human PCa, we utilized small interference RNA (siRNA) to knock down CIP2A expression in human PCa cells and analyzed their phenotypic changes. The data demonstrated that CIP2A was significantly elevated in mCRPC cell lines C4-2 and ARCaP M at both the mRNA and protein levels. CIP2A silencing led to decreased proliferation and enhanced chemosensitivity and apoptosis to cabazitaxel in human PCa cells, as well as reduced Akt phosphorylation. Our data suggesting critical roles of CIP2A in PCa cells chemoresistance to cabazitaxel and raising the possibility of CIP2A inhibition as a promising approach for chemosensitization of metastatic castration-resistant prostate cancer (mCRPC).

To explore the antitumor effect of caffeic acid 3,4-dihydroxy-phenethyl ester (CADPE) on the breast cancer cell lines and illuminate the related mechanism. After treatment with different concentrations of CADPE for 24, 48, and 72 h, cell proliferation ability of the breast cancer cell lines MDA-MB-231 and MDA-MB-435 was analyzed by the MTT. Changes of the cell cycles were evaluated by PI staining. Cell apoptosis was examined by flow cytometry after Annexin V/7AAD double staining. Nuclear morphologic changes were observed under the inverted fluorescence microscope after staining with Hoechst 33342. Mitochondrial membrane potential and reactive oxygen species (ROS) level were estimated by JC-1 and DCFH-DA staining. In addition, the expression level of mitochondrial signaling pathway proteins Bcl-2, Bax, and caspase-3 were evaluated by Western blot. CADPE has the distinct cytotoxic effect to the breast cancer cells, and the effect is dose dependent. It did not change the cell cycles but induced the cell apoptosis of the breast cancer cells. At the same time, after CADPE treatment, the expression levels of caspase-3 and Bax in the breast cancer cells were upregulated and Bcl-2 expression was declined. The ROS level in the breast cancer cells was enhanced, and mitochondrial membrane potential of the cells was downregulated. CADPE has the antitumor functions. It can induce the cell apoptosis through downregulating Bcl-2 expression, enhancing Bax and caspase-3 expression levels, upregulating ROS level and reducing the mitochondrial membrane potential of the breast cancer cells to trigger the mitochondrial signal pathway.

Cancer Biotherapy and Radiopharmaceuticals (CBR) is officially retracting the published article by Mei Yang, Xueyao Wang, Jiaoyuan Jia, Hongwen Gao, Peng Chen, Xianliang Sha, and Shan Wu entitled, “Tumor Protein D52-Like 2 Contributes to Proliferation of Breast Cancer Cells,” Cancer Biother Radiopharm February 2015, 30(1): 1–7. doi:10.1089/cbr.2014.1723. The editors of CBR received a letter from an investigator raising concerns regarding this published paper. Upon examining the 5′-GCGG... shRNA sequence described in the article, the investigator discovered that the lentiviral sequence cited to serve as a “non-silencing” control in fact shows homology to the human TPD52L2 gene (as per a Blastn search conducted by the investigator). The investigator claimed that the article therefore reported the results of knocking down the TPD52L2 gene as both the gene of interest and the supposed negative control. The investigator's concern was such that since the article employed an incorrect control lentiviral construct, the experimental results reported must be invalid. The editors of the CBR contacted the authors of the published paper who confirmed that the sequence was wrong which may have occurred due to a “copy paste error,” and agreed that the report could be misleading and agreed to retract the paper from the literature.