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ATM and chemoresistance

Xiang Zhang, Zhen Zhang, Qing Zhang, Quansheng Zhang, Peiqing Sun, Rong Xiang, Guosheng Ren, Shuang Yang
Although zinc finger E-box binding homeobox 1 (ZEB1) has been identified as a key factor in the regulation of breast cancer differentiation and metastasis, its potential role in modulating tumor chemoresistance has not been fully understood. Here, through the study of specimens from a large cohort of human breast cancer subjects, we showed that patients with tumors that expressed high levels of ZEB1 responded poorly to chemotherapy. Moreover, ZEB1 expression was positively correlated with expression of B-cell lymphoma-extra large (Bcl-xL) and cyclin D1, which are key components of tumor chemoresistant mechanisms...
January 19, 2018: Cell Death & Disease
Hailong Tang, Mimi Shu, Bo Dai, Li Xu, Baoxia Dong, Guangxun Gao, Xiequn Chen
Acquisition of chemoresistance accounts for a major cause of chemotherapy failure for multiple myeloma (MM). Bone marrow stromal cells (BMSCs) are considered to play a pivotal role in modulating drug resistance of MM cells. However, the underlying mechanism whereby BMSCs, particularly damaged stromal cells, affects chemoresistance has not been identified yet. Here, we show exposure to doxorubicin doxorubicin (Dox) induced dramatic ATM (ataxia-telangiectasia-mutated)-dependent DNA damage response (DDR) and increased secretion of interleukin (IL)-6 in HS-5 cell line and primary BMSCs derived from healthy donors...
December 18, 2017: Leukemia & Lymphoma
Wenjun Wang, Minzhang Guo, Xiaojun Xia, Chao Zhang, Yuan Zeng, Sipei Wu
X-ray radiation resistance associated 1 (XRRA1) has been found to regulate the response of human tumor and normal cells to X-radiation (XR). Although XRRA1 overexpression is known to be involved in cancer cell response to XR, there are no reports about whether the expression of XRRA1 in tumors can adjust radioresistance. It is widely known that cell cycle arrest could cause radioresistance. We found that blocked XRRA1 expression could lead to cell cycle G2/M arrest by the regulation of cyclin A, cyclin E, and p21 proteins in colorectal cancer (CRC) and expression of XRRA1 reduced cell cycle arrest and increased cell proliferation in CRC...
2017: BioMed Research International
Angelo Agathanggelou, Edward Smith, Nicholas J Davies, Marwan Kwok, Anastasia Zlatanou, Ceri E Oldreive, Jingwen Mao, David Da Costa, Sina Yadollahi, Tracey Perry, Pamela Kearns, Anna Skowronska, Elliot Yates, Helen Parry, Peter Hillmen, Celine Reverdy, Remi Delansorne, Shankara Paneesha, Guy Pratt, Paul Moss, A Malcolm R Taylor, Grant S Stewart, Tatjana Stankovic
The role of deubiquitylase ubiquitin-specific protease 7 (USP7) in the regulation of the p53-dependent DNA damage response (DDR) pathway is well established. Whereas previous studies have mostly focused on the mechanisms underlying how USP7 directly controls p53 stability, we recently showed that USP7 modulates the stability of the DNA damage responsive E3 ubiquitin ligase RAD18. This suggests that targeting USP7 may have therapeutic potential even in tumors with defective p53 or ibrutinib resistance. To test this hypothesis, we studied the effect of USP7 inhibition in chronic lymphocytic leukemia (CLL) where the ataxia telangiectasia mutated (ATM)-p53 pathway is inactivated with relatively high frequency, leading to treatment resistance and poor clinical outcome...
July 13, 2017: Blood
Qiao Qiao, Chaonan Sun, Chuyang Han, Ning Han, Miao Zhang, Guang Li
Endoplasmic reticulum stress (ERS) plays an important role in the pathogenesis and development of malignant tumors, as well as in the regulation of radiochemoresistance and chemoresistance in many malignancies. ERS signaling pathway protein kinase RNA-like endoplasmic reticulum kinase (PERK)-eukaryotic initiation factor-2 (eIF2α) may induce aberrant activation of nuclear factor-κB (NF-κB). Our previous study showed that NF-κB conferred radioresistance in lymphoma cells. However, whether PERK-eIF2α regulates radioresistance in oropharyngeal carcinoma through NF-κB activation is unknown...
July 2017: Cancer Science
Cristiana Ercolani, Anna Di Benedetto, Irene Terrenato, Laura Pizzuti, Luigi Di Lauro, Domenico Sergi, Francesca Sperati, Simonetta Buglioni, Maria Teresa Ramieri, Lucia Mentuccia, Teresa Gamucci, Letizia Perracchio, Edoardo Pescarmona, Marcella Mottolese, Maddalena Barba, Patrizia Vici, Ruggero De Maria, Marcello Maugeri-Saccà
The Hippo kinases MST1/2 and LATS1/2 inhibit the oncoproteins TAZ/YAP and regulate T cell function. Hippo kinases also cooperate with the ATR-Chk1 and ATM-Chk2 pathways, central orchestrators of the DNA damage response (DDR). We hypothesized that MST1/2 and LATS1/2 localization differently impacts the efficacy of neoadjuvant therapy (NAT) in breast cancer, being protective when expressed in the cytoplasm of tumor cells and in tumor-infiltrating lymphocytes, whereas representing molecular determinants of chemoresistance when present in the nucleus as a consequence of their cooperation with the DDR...
May 4, 2017: Cancer Biology & Therapy
Xiaozhou Hu, Esra Baytak, Jinnan Li, Burcu Akman, Kaan Okay, Genfu Hu, Anna Scuto, Wenyan Zhang, Can Küçük
Follicular lymphoma (FL) is a common type of indolent lymphoma that occasionally transforms to more aggressive B-cell lymphomas. These transformed follicular lymphomas (tFL) are often associated with chemoresistance whose mechanisms are currently unknown. REL, a proto-oncogene located on frequently amplified 2p16.1-p15 locus, promotes tumorigenesis in many cancer types through deregulation of the NF-κB pathway; however, its role in FL pathobiology or chemoresistance has not been addressed. Here, we evaluated REL gene copy number by q-PCR on FFPE FL tumor samples, and observed REL amplification in 30...
March 2017: Leukemia Research
Shanaya Patel, Rakesh Rawal
Late diagnosis, low therapeutic response, and metastasis are accountable for poor 5-year survival rate of OSCC. These failures are attributed to the existence of "cancer stem cell (CSC)" subpopulation. Hence, it is necessary to identify and understand the mechanism of CSCs in tumor development, metastasis, and chemotherapeutic response. Propelling evidences suggest that microRNA (miRNA)-mediated regulation and cytokines of tumor microenvironment have the ability to modulate CSC signalling pathway; however, their exact mechanism needs to be elucidated...
November 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Shuqing Li, Lina Yang, Jingshu Wang, Fan Liang, Bin Chang, Huafen Gu, Honglin Wang, Gong Yang, Yaping Chen
Epithelial ovarian cancer is most lethal in female reproductive carcinomas owing to the high chemoresistance and metastasis, so more efficient therapeutic agents are terribly needed. A propadiene compound: 1-phenylpropadienyl phosphine oxide (PHPO), was employed to test the chemotherapeutic efficacy against ovarian cancer cell lines. MTT assay showed that PHPO displayed a much lower IC50 than cisplatin and paclitaxel, while combination treatment of cells with PHPO + cisplatin induced more apoptosis than with PHPO + paclitaxel or with cisplatin + paclitaxel (p < 0...
August 30, 2016: Oncotarget
Kellen Cristine Tjioe, Denise Tostes Oliveira, Julie Gavard
Oral squamous cell carcinoma (OSCC) exhibited high chemoresistance to current treatments. Here we aimed at identifying and repositioning approved drugs that could be selectively toxic toward OSCC cells. Through a cell-based drug screening of 1,280 chemical molecules, we selected compounds lethal to oral cancer SCC-25 cells, while sparing normal keratinocyte HaCaT cells. Within the chemical library, the natural flavonoid luteolin was identified as a potent cytotoxic agent against oral cancer cells in vitro, along with metixene hydrochloride and nitazoxanide...
July 2016: Nutrition and Cancer
Khanh V Luong, Ling Wang, Brett J Roberts, James K Wahl, Aimin Peng
Understanding the determination of cell fate choices after cancer treatment will shed new light on cancer resistance. In this study, we quantitatively analyzed the individual cell fate choice in resistant UM-SCC-38 head and neck cancer cells exposed to cisplatin. Our study revealed a highly heterogeneous pattern of cell fate choices in UM-SCC-38 cells, in comparison to that of the control, non-tumorigenic keratinocyte HaCaT cells. In both UM-SCC-38 and HaCaT cell lines, the majority of cell death occurred during the immediate interphase without mitotic entry, whereas significant portions of UM-SCC-38 cells survived the treatment via either checkpoint arrest or checkpoint slippage...
April 26, 2016: Oncotarget
Jayadev Mavuluri, Swarnalatha Beesetti, Rohan Surabhi, Joachim Kremerskothen, Ganesh Venkatraman, Suresh K Rayala
Multifunctional adaptor proteins encompassing various protein-protein interaction domains play a central role in the DNA damage response pathway. In this report, we show that KIBRA is a physiologically interacting reversible substrate of ataxia telangiectasia mutated (ATM) kinase. We identified the site of phosphorylation in KIBRA as threonine 1006, which is embedded within the serine/threonine (S/T) Q consensus motif, by site-directed mutagenesis, and we further confirmed the same with a phospho-(S/T) Q motif-specific antibody...
May 2016: Molecular and Cellular Biology
Marwan Kwok, Nicholas Davies, Angelo Agathanggelou, Edward Smith, Eva Petermann, Eliot Yates, Jeffrey Brown, Alan Lau, Tatjana Stankovic
BACKGROUND: DNA damage response (DDR) defects, particularly TP53 and biallelic ataxia telangiectasia mutated (ATM) aberrations, are associated with genomic instability, clonal evolution, and chemoresistance in chronic lymphocytic leukaemia (CLL). Therapies capable of providing long-term disease control in CLL patients with DDR defects are lacking. Using AZD6738, a novel ATR inhibitor, we investigated ATR pathway inhibition as a synthetically lethal strategy for targeting CLL cells with these defects...
February 26, 2015: Lancet
G D te Raa, P D Moerland, A C Leeksma, I A Derks, H Yigittop, N Laddach, M Loden-van Straaten, V Navrkalova, M Trbusek, D M Luijks, T Zenz, A Skowronska, M Hoogendoorn, T Stankovic, M H van Oers, E Eldering, A P Kater
The ATM-p53 DNA-damage response (DDR) pathway has a crucial role in chemoresistance in CLL, as indicated by the adverse prognostic impact of genetic aberrations of TP53 and ATM. Identifying and distinguishing TP53 and ATM functional defects has become relevant as epigenetic and posttranscriptional dysregulation of the ATM/p53 axis is increasingly being recognized as the underlying cause of chemoresistance. Also, specific treatments sensitizing TP53- or ATM-deficient CLL cells are emerging. We therefore developed a new ATM-p53 functional assay with the aim to (i) identify and (ii) distinguish abnormalities of TP53 versus ATM and (iii) enable the identification of additional defects in the ATM-p53 pathway...
2015: Cell Death & Disease
Hiroaki Ono, Marc D Basson, Hiromichi Ito
UNLABELLED: Protein Tyrosine Kinase 6 (PTK6) is a non-receptor-type tyrosine kinase known to be expressed in various cancers, including pancreatic cancer. The role of PTK6 in cancer chemoresistance remains unclear. Therefore, it was hypothesized that PTK6 mechanistically regulates gemcitabine resistance in pancreatic cancer. Gemcitabine treatment stimulated endogenous PTK6 overexpression in MIAPaCa2 and Panc1 cells. PTK6 gene silencing increased cell survival after gemcitabine treatment and decreased apoptosis, whereas PTK6 overexpression decreased cell survival and increased apoptosis...
August 2015: Molecular Cancer Research: MCR
Stian Knappskog, Elisabet O Berge, Ranjan Chrisanthar, Stephanie Geisler, Vidar Staalesen, Beryl Leirvaag, Synnøve Yndestad, Elise de Faveri, Bård O Karlsen, David C Wedge, Lars A Akslen, Peer K Lilleng, Erik Løkkevik, Steinar Lundgren, Bjørn Østenstad, Terje Risberg, Ingvild Mjaaland, Turid Aas, Per E Lønning
Chemoresistance is the main obstacle to cancer cure. Contrasting studies focusing on single gene mutations, we hypothesize chemoresistance to be due to inactivation of key pathways affecting cellular mechanisms such as apoptosis, senescence, or DNA repair. In support of this hypothesis, we have previously shown inactivation of either TP53 or its key activators CHK2 and ATM to predict resistance to DNA damaging drugs in breast cancer better than TP53 mutations alone. Further, we hypothesized that redundant pathway(s) may compensate for loss of p53-pathway signaling and that these are inactivated as well in resistant tumour cells...
October 2015: Molecular Oncology
Xinsen Ruan, Qiao Zuo, Hao Jia, Jenny Chau, Jinlin Lin, Junping Ao, Xuechun Xia, Huijuan Liu, Samy L Habib, Chuangang Fu, Baojie Li
The DNA damage response helps to maintain genome integrity, suppress tumorigenesis, and mediate the effects of radiotherapy and chemotherapy. Our previous studies have shown that Smad1 is upregulated and activated by Atm in DNA damage response, which can further bind to p53 and promote p53 stabilization. Here we report another aspect of the interplay between p53 and Smad1. Comparison of rectal tumor against paired paraneoplastic specimens and analysis of >500 colorectal tumors revealed that Smad1 was upregulated in tumor samples, which was attributable to p53 defects...
April 2015: Journal of Molecular Cell Biology
Yiqian Zhang, Chunling Jiang, Huilan Li, Feng Lv, Xiaoyan Li, Xiaolong Qian, Li Fu, Bo Xu, Xiaojing Guo
Aurora-B is a major kinase responsible for appropriate mitotic progression. Elevated expression of Aurora-B has been frequently associated with several types of cancer, including breast cancer. However, it is not clear whether the alteration contributes to tumor responses to therapies and prognosis. In this study, we conducted immunohistochemistry using antibodies against Aurora-B, S1981p-ATM, Ki67, and p53 in paraffin-embedded tumor tissues from 312 invasive breast cancer patients. The correlation between disease-free-survival (DFS) and Aurora-B expression was analyzed using the Kaplan-Meier method and log-rank test...
2015: International Journal of Clinical and Experimental Pathology
Sandra M Ehrlich, Johanna Liebl, Maximilian A Ardelt, Thorsten Lehr, Enrico N De Toni, Doris Mayr, Lydia Brandl, Thomas Kirchner, Stefan Zahler, Alexander L Gerbes, Angelika M Vollmar
BACKGROUND & AIMS: For a long time cyclin dependent kinase 5 (Cdk5) was thought to be exclusively important in neuronal cells. However, increasing evidence recently suggests a function of Cdk5 in cancer progression. In this study, we examined the role of Cdk5 and its therapeutic accessibility in hepatocellular carcinoma (HCC), a highly chemoresistant cancer with poor prognosis and paramount clinical importance in order to develop novel targeted therapies for systemic treatment. METHODS: Expression and activity of Cdk5 was analyzed in a human HCC tissue microarray, human patient samples and HCC cell lines...
July 2015: Journal of Hepatology
Daniela D'Angelo, Paula Mussnich, Roberta Rosa, Roberto Bianco, Giampaolo Tortora, Alfredo Fusco
BACKGROUND: Development of resistance to conventional drugs and novel biological agents often impair long-term chemotherapy. HMGA gene overexpression is often associated with antineoplastic drug resistance and reduced survival. Inhibition of HMGA expression in thyroid cancer cells reduces levels of ATM protein, the main cellular sensor of DNA damage, and enhances cellular sensitivity to DNA-damaging agents. HMGA1 overexpression promotes chemoresistance to gemcitabine in pancreatic adenocarcinoma cells through an Akt-dependent mechanism...
November 20, 2014: BMC Cancer
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