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.

Different pyruvate kinase isoforms are expressed in a tissue-specific manner, with pyruvate kinase M2 (PKM2) suggested to be the predominant isoform in proliferating cells and cancer cells. Due to differential regulation of enzymatic activities, PKM2 but not PKM1 has been thought to favor cell proliferation. However, the role of PKM2 in tumorigenesis has been recently challenged. Here we report that increased glucose catabolism through glycolysis and increased pyruvate kinase activity in c-MYC-driven liver tumors are associated with increased expression of both PKM1 and PKM2 isoforms and decreased expression of the liver-specific isoform of pyruvate kinase, PKL. Depletion of PKM2 at the time of c-MYC over-expression in murine livers did not affect c-MYC induced tumorigenesis and resulted in liver tumor formation with decreased pyruvate kinase activity and decreased catabolism of glucose into alanine and the Krebs cycle. An increased PKM1/PKM2 ratio by ectopic PKM1 expression further decreased glucose flux into serine biosynthesis and increased flux into lactate and the Krebs cycle, resulting in reduced total levels of serine. However, these changes also did not affect c-MYC-induced liver tumor development. These results suggest that increased expression of PKM2 is not required to support c-MYC-induced tumorigenesis in the liver and that various PKM1/PKM2 ratios and pyruvate kinase activities can sustain glucose catabolism required for this process.

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.

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.

Cancer Biotherapy and Radiopharmaceuticals (CBR) is officially retracting the published article by

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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.

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).