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Saketh S Dinavahi, Mohammed A Noory, Raghavendra Gowda, Joseph J Drabick, Rogerio I Neves, Arthur Berg, Gavin P Robertson
Drug combinations acting synergistically to kill cancer cells have become increasingly important in melanoma as an approach to manage the recurrent resistant disease. AKT is a major target in this disease but its inhibitors are not effective clinically, which is a major concern. Targeting AKT in combination with WEE1 seems to have potential to make AKT based therapeutics effective clinically. Since agents targeting AKT and WEE1 have been tested individually in the clinic, the quickest way to move the drug combination to patients would be to combine them sequentially, enabling the use of existing phase-I clinical trial toxicity data...
December 14, 2017: Molecular Pharmacology
Gerd A Müller, Konstanze Stangner, Thomas Schmitt, Axel Wintsche, Kurt Engeland
A central question in cell cycle control is how differential gene expression is regulated. Timing of expression is important for correct progression through the cell cycle. E2F, CDE, and CHR promoter sites have been linked to transcriptional repression in resting cells and activation during the cell cycle. Further, the DREAM complex binds CHR or CDE/CHR elements of G2/M genes resulting in repression during G0/G1. Here, we show that DREAM also binds to E2F sites of S phase genes in quiescence and upon p53 activation...
November 17, 2017: Oncotarget
Sanaz Taromi, Florentine Lewens, Ruza Arsenic, Dagmar Sedding, Jörg Sänger, Almut Kunze, Markus Möbs, Joana Benecke, Helma Freitag, Friederike Christen, Daniel Kaemmerer, Amelie Lupp, Mareike Heilmann, Hedwig Lammert, Claus-Peter Schneider, Karen Richter, Michael Hummel, Britta Siegmund, Meike Burger, Franziska Briest, Patricia Grabowski
Small cell lung cancer (SCLC) is an aggressive cancer showing a very poor prognosis because of metastasis formation at an early stage and acquisition of chemoresistance. One key driver of chemoresistance is the transcription factor Forkhead box protein M1 (FOXM1) that regulates cell cycle proliferation, maintenance of genomic stability, DNA damage response, and cell differentiation in numerous tumor entities. In this study we investigated the role of FOXM1 in SCLC progression and analyzed the effect of FOXM1 inhibition using two proteasome inhibitors, bortezomib and siomycin A...
November 14, 2017: Oncotarget
Bridgette F Peake, Siobhan M Eze, Lily Yang, Robert C Castellino, Rita Nahta
Expression of the inflammatory cytokine growth differentiation factor 15 (GDF15) is significantly elevated in many tumor types in association with epithelial mesenchymal transition (EMT), drug resistance, and progressive disease. However, few studies have examined GDF15 expression, signaling, or function in breast cancer. In the current study, we demonstrate that GDF15 is associated with high tumor grade, ER-negativity, and HER2 overexpression in patients with breast cancer. Stable overexpression of GDF15 upregulates expression of mesenchymal markers and transcription factors, including FoxM1, and increases cellular invasion...
November 7, 2017: Oncotarget
Junpei Yamamoto, Junta Imai, Tomohito Izumi, Hironori Takahashi, Yohei Kawana, Kei Takahashi, Shinjiro Kodama, Keizo Kaneko, Junhong Gao, Kenji Uno, Shojiro Sawada, Tomoichiro Asano, Vladimir V Kalinichenko, Etsuo A Susaki, Makoto Kanzaki, Hiroki R Ueda, Yasushi Ishigaki, Tetsuya Yamada, Hideki Katagiri
Under insulin-resistant conditions such as obesity, pancreatic β-cells proliferate to prevent blood glucose elevations. A liver-brain-pancreas neuronal relay plays an important role in this process. Here, we show the molecular mechanism underlying this compensatory β-cell proliferation. We identify FoxM1 activation in islets from neuronal relay-stimulated mice. Blockade of this relay, including vagotomy, inhibits obesity-induced activation of the β-cell FoxM1 pathway and suppresses β-cell expansion. Inducible β-cell-specific FoxM1 deficiency also blocks compensatory β-cell proliferation...
December 5, 2017: Nature Communications
Yosuke Inoue, Kazumasa Moriwaki, Yasuhiro Ueda, Toshihisa Takeuchi, Kazuhide Higuchi, Michio Asahi
O-GlcNAcylation is a dynamic post-translational modification of cytonuclear proteins for intracellular signaling. Elevated O-GlcNAcylation is a general feature of cancer and contributes to cancer progression, and recent studies indicate the contribution to increasing incidence of various types of cancer in diabetic patients. However, the role of O-GlcNAcylation in tumor progression is not fully elucidated. Forkhead box M1 (FOXM1), a master mitotic transcription factor, has been implicated in all major hallmarks of cancer, and is wildly expressed in solid tumors...
November 28, 2017: Biochemical and Biophysical Research Communications
Yoshihiro Ishida, Atsushi Otsuka, Kenji Kabashima
PURPOSE OF REVIEW: The present review aims to provide readers with the latest updates on the biology and clinical management of cutaneous angiosarcoma (cAS). RECENT FINDINGS: The genomic alteration of cAS is heterogeneous. Mutations are enriched in the mitosis-activated kinase (MAPK) pathway. Functional analysis has identified molecules that may serve as potential markers and therapeutic targets of angiosarcoma. These molecules include survivin, HSP90, FOXM1, miR-497-5p, KCa3...
November 30, 2017: Current Opinion in Oncology
In-Sung Song, Yu Jeong Jeong, Young Jin Seo, Jung Mi Byun, Young Nanm Kim, Dae Hoon Jeong, Jin Han, Ki Tae Kim, Sung-Wuk Jang
Cancer stem cell (CSC)-targeted therapy could reduce tumor growth, recurrence, and metastasis in endometrial cancer (EC). The mitochondria of CSCs have been recently found to be an important target for cancer treatment, but the mitochondrial features of CSCs and their regulators, which maintain mitochondrial function, remain unclear. Here, we investigated the mitochondrial properties of CSCs, and identified specific targets for eliminating CSCs in EC. We found that endometrial CSCs displayed higher mitochondrial membrane potential, Ca2+, reactive oxygen species, ATP levels, and oxygen consumption rates than non-CSCs...
November 3, 2017: Oncotarget
Wenzheng Fang, Jianxin Qian, Qing Wu, Ying Chen, Guanzhen Yu
BACKGROUND: The ADAMs proteases are a multifunctional family of proteins, many of which participate in the pathogenesis of cancers. The expression and regulation of ADAMs has not yet been fully examined in gastric cancer. MATERIALS AND METHODS: Using reverse transcription-PCR, messenger RNA expression of ADAM-9, ADAM-10, ADAM-11, ADAM-12, ADAM-15, ADAM-17, ADAM-28, and ADAM-33 was detected in gastric cancer. ADAM-10, ADAM-17, ADAM-28, and FoxM1 expression in gastric cancer was detected by Western blot and immunohistochemistry...
December 2017: Journal of Surgical Research
Shang Yao, Lavender Yuen-Nam Fan, Eric Wing-Fai Lam
The FOXO3 and FOXM1 forkhead box transcription factors, functioning downstream of the essential PI3K-Akt, Ras-ERK and JNK/p38MAPK signalling cascades, are crucial for cell proliferation, differentiation, cell survival, senescence, DNA damage repair and cell cycle control. The development of resistance to both conventional and newly emerged molecularly targeted therapies is a major challenge confronting current cancer treatment in the clinic. Intriguingly, the mechanisms of resistance to 'classical' cytotoxic chemotherapeutics and to molecularly targeted therapies are invariably linked to deregulated signalling through the FOXO3 and FOXM1 transcription factors...
November 24, 2017: Seminars in Cancer Biology
Xue Yang, Kai Qu, Jie Tao, Guozhi Yin, Shaoshan Han, Qingguang Liu, Hao Sun
CIP2A is a recent identified oncogene that inhibits protein phosphatase 2A (PP2A) and stabilizes c-Myc in cancer cells. To investigate the potential oncogenic role and prognostic value of CIP2A, we comprehensively analyzed the CIP2A expression levels in pan-cancer and observed high expression level of CIP2A in majority cancer types, including hepatocellular carcinoma (HCC). Based on a validation cohort including 60 HCC and 20 non-tumorous tissue samples, we further confirmed the high mRNA and protein expression levels of CIP2A in HCC, and found high CIP2A mRNA expression level was associated with unfavorable overall and recurrence-free survival in patients with HCC...
November 21, 2017: Biochemical and Biophysical Research Communications
Bao-Ying Fei, Xujun He, Jie Ma, Mei Zhang, Rui Chai
The aim of the present study was to investigate the role of forkhead box M1 (FoxM1) in epithelial-mesenchymal transition (EMT) and metastasis in colorectal cancer (CRC). Immunohistochemical assays were performed to detect FoxM1 and epithelial (E-) cadherin protein expression in 92 CRC, 61 colonic adenoma and 32 wild-type colonic tissue samples. Quantitative polymerase chain reaction (qPCR) assays were performed to determine the expression levels of FoxM1 and E-cadherin mRNAs in 30 CRC and adjacent normal mucosal tissues...
December 2017: Oncology Letters
Gaohui Wu, Liteng Yang, Yi Xu, Xiaohong Jiang, Xiaomin Jiang, Lisha Huang, Ling Mao, Shaoxi Cai
Functional abnormal airway epithelial cells, along with activated inflammatory cells, resulting in chronic airway inflammation, are considered as the characteristic of asthma. Fatty Acid Binding Protein 4 (FABP4) takes part in glucose and lipid homeostasis, and also have an important role in allergic airway inflammation. However, whether FABP4 influence barrier function of airway epithelial cells is unknown. In vivo, a HDM-induced murine model of asthma was obtained to assessed airway inflammation and protein expression of E-cadherin and Forkhead Box M1 (FoxM1)...
November 17, 2017: Biochemical and Biophysical Research Communications
Jai-Sing Yang, Chao-Ying Lee, Hsin-Chung Cho, Chi-Cheng Lu, Sheng-Chu Kuo, Yen-Fang Wen, Fuu-Jen Tsai, Miau-Rong Lee, Shih-Chang Tsai
ITR‑284 is a carboxamide analog that can inhibit proliferation in human promyelocytic leukemia HL-60 cells. To understand the effects and molecular mechanisms of ITR‑284 in human erythromyeloblastoid leukemia, we treated K562 cells with different concentrations of ITR‑284 (0, 2, 4, 6, 8 and 10 nM) and all-trans retinoic acid (ATRA) (0, 0.1, 0.5, 1, 5 and 10 µM) for 24 h. The IC50 of ITR‑284 was ~10 nM in K562 cells treated for 24 h as determined by MTT assay. May-Grünwald-Giemsa staining and nitro blue tetrazolium (NBT) assays were used to determine cell morphology changes and differentiation after ITR‑284 and ATRA treatment...
November 9, 2017: Oncology Reports
Lijiang Zhao, Lijuan Liu, Zheng Dong, Jie Xiong
Valid evidence has demonstrated that microRNAs have critical functions in cancer genesis and tumor progression. In the present study, aberrant expression of microRNA-149 (miR-149) was confirmed in non-small cell lung cancer (NSCLC) tissues. Low expression of miR-149 was associated with malignant clinical features and poor survival. Gain- and loss-of-function experiments demonstrated that miR-149 inhibited NSCLC tumor growth and metastasis in vitro and in vivo. Furthermore, oncogenic transcription factor FOXM1 was confirmed as a direct target of miR-149 in NSCLC...
December 2017: Oncology Reports
Arnold Bolomsky, Roy Heusschen, Karin Schlangen, Kathrin Stangelberger, Joséphine Muller, Wolfgang Schreiner, Niklas Zojer, Jo Caers, Heinz Ludwig
Treatment of high-risk patients is a major challenge in multiple myeloma. This is especially true for patients assigned to the gene-expression-profiling defined proliferation subgroup. Although recent efforts have identified some key players of proliferative myeloma, genetic interactions and players that can be targeted with clinically effective drugs have to be identified to overcome the poor prognosis of these patients. We therefore examined maternal embryonic leucine zipper kinase (MELK) for its implications in hyper-proliferative myeloma and analysed the activity of the MELK inhibitor OTSSP167 in vitro and in vivo...
November 9, 2017: Haematologica
Yue Wang, Matthew H Ung, Tian Xia, Wenqing Cheng, Chao Cheng
ChIP-seq has been commonly applied to identify genomic occupation of transcription factors (TFs) in a context-specific manner. It is generally assumed that a TF should have similar binding patterns in cells from the same or closely related tissues. Surprisingly, this assumption has not been carefully examined. To this end, we systematically compared the genomic binding of the cell cycle regulator FOXM1 in eight cell lines from seven different human tissues at binding signal, peaks and target genes levels. We found that FOXM1 binding in ER-positive breast cancer cell line MCF-7 are distinct comparing to those in not only other non-breast cell lines, but also MDA-MB-231, ER-negative breast cancer cell line...
September 29, 2017: Oncotarget
Raquel Torres-Guzmán, Bruna Calsina, Ana Hermoso, Carmen Baquero, Beatriz Alvarez, Joaquín Amat, Ann M McNulty, Xueqian Gong, Karsten Boehnke, Jian Du, Alfonso de Dios, Richard P Beckmann, Sean Buchanan, María José Lallena
Abemaciclib is an ATP-competitive, reversible kinase inhibitor selective for CDK4 and CDK6 that has shown antitumor activity as a single agent in hormone receptor positive (HR+) metastatic breast cancer in clinical trials. Here, we examined the mechanistic effects of abemaciclib treatment using in vitro and in vivo breast cancer models. Treatment of estrogen receptor positive (ER+) breast cancer cells with abemaciclib alone led to a decrease in phosphorylation of Rb, arrest at G1, and a decrease in cell proliferation...
September 19, 2017: Oncotarget
Qing Ma, Yanmei Liu, Liang Shang, Jiao Yu, Qiumin Qu
Accumulating evidence indicates that mitotic checkpoint serine/threonine kinase B (BUB1B) plays a critical role in multiple types of cancer. However, the biological function and molecular regulatory mechanism of BUB1B in glioblastoma (GBM) remain unclear. In the present study, we identified that BUB1B expression was enriched in GBM tumors and was functionally required for tumor proliferation both in vitro and in vivo. Clinically, BUB1B expression was associated with poor prognosis in GBM patients and BUB1B‑dependent radioresistance in GBM was decreased by targeting BUB1B via shRNAs...
October 12, 2017: Oncology Reports
Dongdong Jiang, Lu Jiang, Baiying Liu, He Huang, Wenbin Li, Taotao Zhang, Guo Zu, Xiangwen Zhang
BACKGROUND: The relationship between expression of FoxM1 and clinical parameters of patients with gastric cancer (GC) has yet to be fully established. METHODS: A systematic search was performed. Odds ratio (OR) and confidence interval (CI) were used to assess association between expression of FoxM1 and clinical parameters and the prognostic value of patients with GC. RESULTS: Eight studies involving 529 patients with GC were identified. Overall, the pooled results showed that expression of FoxM1 was associated with TNM stage (OR: 0...
October 7, 2017: International Journal of Surgery
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