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ATM and chemoresistance

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https://www.readbyqxmd.com/read/27612478/role-of-mirna-dynamics-and-cytokine-profile-in-governing-cd44v6-nanog-pten-axis-in-oral-cancer-modulating-the-master-regulators
#1
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...
September 9, 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
https://www.readbyqxmd.com/read/27494891/analysis-of-the-chemotherapeutic-effects-of-a-propadiene-compound-on-malignant-ovarian-cancer-cells
#2
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 2, 2016: Oncotarget
https://www.readbyqxmd.com/read/27266882/luteolin-impacts-on-the-dna-damage-pathway-in-oral-squamous-cell-carcinoma
#3
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
https://www.readbyqxmd.com/read/26993599/cell-fate-determination-in-cisplatin-resistance-and-chemosensitization
#4
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
https://www.readbyqxmd.com/read/26929199/phosphorylation-dependent-regulation-of-the-dna-damage-response-of-adaptor-protein-kibra-in-cancer-cells
#5
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
https://www.readbyqxmd.com/read/26312880/synthetic-lethality-in-chronic-lymphocytic-leukaemia-with-dna-damage-response-defects-by-targeting-the-atr-pathway
#6
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
https://www.readbyqxmd.com/read/26247737/assessment-of-p53-and-atm-functionality-in-chronic-lymphocytic-leukemia-by-multiplex-ligation-dependent-probe-amplification
#7
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
https://www.readbyqxmd.com/read/26013168/ptk6-potentiates-gemcitabine-induced-apoptosis-by-prolonging-s-phase-and-enhancing-dna-damage-in-pancreatic-cancer
#8
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
https://www.readbyqxmd.com/read/26004085/concomitant-inactivation-of-the-p53-and-prb-functional-pathways-predicts-resistance-to-dna-damaging-drugs-in-breast-cancer-in%C3%A2-vivo
#9
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
https://www.readbyqxmd.com/read/25757624/p53-deficiency-induced-smad1-upregulation-suppresses-tumorigenesis-and-causes-chemoresistance-in-colorectal-cancers
#10
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
https://www.readbyqxmd.com/read/25755770/elevated-aurora-b-expression-contributes-to-chemoresistance-and-poor-prognosis-in-breast-cancer
#11
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
https://www.readbyqxmd.com/read/25660209/targeting-cyclin-dependent-kinase-5-in-hepatocellular-carcinoma-a-novel-therapeutic-approach
#12
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
https://www.readbyqxmd.com/read/25409711/high-mobility-group-a1-protein-expression-reduces-the-sensitivity-of-colon-and-thyroid-cancer-cells-to-antineoplastic-drugs
#13
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
https://www.readbyqxmd.com/read/25310623/5%C3%A2-fu-resistance-abrogates-the-amplified-cytotoxic-effects-induced-by-inhibiting-checkpoint-kinase%C3%A2-1-in-p53%C3%A2-mutated-colon-cancer-cells
#14
Tomofumi Akasaka, Masahiko Tsujii, Jumpei Kondo, Yoshito Hayashi, Jin Ying, Yuquan Lu, Motohiko Kato, Takuya Yamada, Shunsuke Yamamoto, Takuya Inoue, Yoshiki Tsujii, Akira Maekawa, Tetsuji Fujinaga, Eri Shiraishi, Satoshi Hiyama, Takahiro Inoue, Shinichiro Shinzaki, Kenji Watabe, Tsutomu Nishida, Hideki Iijima, Tetsuo Takehara
The emergence of chemoresistance is a major limitation of current cancer therapies, and checkpoint kinase (Chk1) 1 positively correlates with resistance to chemo‑ or radio‑therapy. Cancer cells lacking p53 pathways are completely dependent on the S and G2/M checkpoints via Chk1; therefore, Chk1 inhibition enhances the cytotoxicity of DNA‑damaging agents only in p53‑deficient cells. However, little is known about the synergistic effect of Chk1 inhibition with 5‑FU, the most frequently used antimetabolite, in chemoresistant colorectal cells...
January 2015: International Journal of Oncology
https://www.readbyqxmd.com/read/25195859/p57kip2-is-an-unrecognized-dna-damage-response-effector-molecule-that-functions-in-tumor-suppression-and-chemoresistance
#15
H Jia, Q Cong, J F L Chua, H Liu, X Xia, X Zhang, J Lin, S L Habib, J Ao, Q Zuo, C Fu, B Li
The DNA damage response (DDR) helps to maintain genome integrity, suppress tumorigenesis and mediate the radiotherapeutic and chemotherapeutic effects on cancer. Here we report that p57Kip2, a cyclin-dependent kinase (CDK) inhibitor implicated in the development of tumor-prone Beckwith-Wiedemann syndrome, is an effector molecule of the DNA-damage response. Genotoxic stress induces p57Kip2 expression via the bone morphogenetic protein-Smad1 and Atm-p38MAPK-Atf2 pathways in p53-proficient or -deficient cells and requires the Smad1-Atf2 complex that facilitates their recruitment to the p57Kip2 promoter...
July 2015: Oncogene
https://www.readbyqxmd.com/read/25086746/atm-mediated-stabilization-of-zeb1-promotes-dna-damage-response-and-radioresistance-through-chk1
#16
Peijing Zhang, Yongkun Wei, Li Wang, Bisrat G Debeb, Yuan Yuan, Jinsong Zhang, Jingsong Yuan, Min Wang, Dahu Chen, Yutong Sun, Wendy A Woodward, Yongqing Liu, Douglas C Dean, Han Liang, Ye Hu, K Kian Ang, Mien-Chie Hung, Junjie Chen, Li Ma
Epithelial-mesenchymal transition (EMT) is associated with characteristics of breast cancer stem cells, including chemoresistance and radioresistance. However, it is unclear whether EMT itself or specific EMT regulators play causal roles in these properties. Here we identify an EMT-inducing transcription factor, zinc finger E-box binding homeobox 1 (ZEB1), as a regulator of radiosensitivity and DNA damage response. Radioresistant subpopulations of breast cancer cells derived from ionizing radiation exhibit hyperactivation of the kinase ATM and upregulation of ZEB1, and the latter promotes tumour cell radioresistance in vitro and in vivo...
September 2014: Nature Cell Biology
https://www.readbyqxmd.com/read/24988892/interleukin-6-augments-lung-cancer-chemotherapeutic-resistance-via-ataxia-telangiectasia-mutated-nf-kappab-pathway-activation
#17
Hong Qiong Yan, Xiao Bo Huang, Shi Zhong Ke, Yi Na Jiang, Yue Hua Zhang, Yi Nan Wang, Juan Li, Feng Guang Gao
Although it is known that ataxia-telangiectasia mutated (ATM) and interleukin 6 (IL-6) contribute to multiple drug resistance (MDR) in tumor chemotherapy, the exact role of ATM activation in MDR resulting from increased IL-6 expression is still unclear. In the present study, we demonstrate that the activation of the ATM-NF-kappaB pathway, resulting from increased IL-6 expression, plays a central role in augmented chemoresistance in lung cancer cell lines. This result was supported by the increased expressions of Bcl-2, Mcl-1, Bcl-xl, and the upregulation of MDR-associated protein ABCG2...
September 2014: Cancer Science
https://www.readbyqxmd.com/read/24793792/progranulin-promotes-temozolomide-resistance-of-glioblastoma-by-orchestrating-dna-repair-and-tumor-stemness
#18
I Bandey, S-H Chiou, A-P Huang, J-C Tsai, P-h Tu
Glioblastoma multiforme (GBM) is the most common malignant brain tumor in adults with a dismal prognosis. Current therapy of surgical removal combined with Temozolomide (TMZ) and radiation therapy only slightly prolongs the survival of GBM patients. Thus, it is essential to elucidate mechanism underlying its highly malignant properties in order to develop efficacious therapeutic regimens. In this study, we showed that progranulin (PGRN) was overexpressed in most GBM cell lines and the majority of human tumor samples...
April 2, 2015: Oncogene
https://www.readbyqxmd.com/read/24737504/temozolomide-induces-autophagy-via-atm%C3%A2-ampk%C3%A2-ulk1-pathways-in-glioma
#19
Yuhui Zou, Qiong Wang, Bingling Li, Bing Xie, Weimin Wang
Autophagy is a cytoprotective process, which occurs following temozolomide (TMZ) treatment, and contributes to glioma chemoresistance and TMZ treatment failure. However, the molecular mechanisms by which TMZ induces autophagy are largely unknown. In the current study, the ataxia‑telangiectasia mutated (ATM) inhibitor KU‑55933, adenosine monophosphate‑activated protein kinase (AMPK) inhibitor compound C, and U87MG and U251 cell lines were employed to investigate the molecular mechanisms of TMZ‑induced autophagy in glioma, and to evaluate the effects of autophagy inhibition on TMZ cytotoxicity...
July 2014: Molecular Medicine Reports
https://www.readbyqxmd.com/read/24480460/aurora-a-controls-cancer-cell-radio-and-chemoresistance-via-atm-chk2-mediated-dna-repair-networks
#20
Huizhen Sun, Yan Wang, Ziliang Wang, Jiao Meng, Zihao Qi, Gong Yang
High expression of Aurora kinase A (Aurora-A) has been found to confer cancer cell radio- and chemoresistance, however, the underlying mechanism is unclear. In this study, by using Aurora-A cDNA/shRNA or the specific inhibitor VX680, we show that Aurora-A upregulates cell proliferation, cell cycle progression, and anchorage-independent growth to enhance cell resistance to cisplatin and X-ray irradiation through dysregulation of DNA damage repair networks. Mechanistic studies showed that Aurora-A promoted the expression of ATM/Chk2, but suppressed the expression of BRCA1/2, ATR/Chk1, p53, pp53 (Ser15), H2AX, γH2AX (Ser319), and RAD51...
May 2014: Biochimica et Biophysica Acta
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