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https://www.readbyqxmd.com/read/28431397/sensitization-of-tamoxifen-resistant-breast-cancer-cells-by-z-ligustilide-through-inhibiting-autophagy-and-accumulating-dna-damages
#1
Hongyi Qi, Zhuyun Jiang, Chengqiang Wang, Yi Yang, Li Li, Hui He, Zanyang Yu
Autophagy plays a pro-survival role in the tamoxifen-resistant breast cancer cells. Herein we found that autophagy was concomitantly induced in tamoxifen-resistant MCF-7 (MCF-7TR5) cells through the dissociation of Bcl-2 from Beclin 1 and subsequent enhancement of interaction among the ATG14-Beclin1-PI3KC3 complex. Moreover, higher level of DNA damage was observed in MCF-7TR5 cells with the decreased BRCA1 and RAD51 level and the increased Ku80 level. Interestingly, Nur77 was selectively degraded by autophagy, which causes the release of Ku80 from the Nur77-Ku80 complex, resulting in the increase of the DNA binding of Ku80 and DNA-PKcs...
April 4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28423586/the-role-of-ros-and-subsequent-dna-damage-response-in-puma-induced-apoptosis-of-ovarian-cancer-cells
#2
Jun Yang, Xinyu Zhao, Mei Tang, Lei Li, Yi Lei, Ping Cheng, Wenhao Guo, Yu Zheng, Wei Wang, Na Luo, Yong Peng, Aiping Tong, Yuquan Wei, Chunlai Nie, Zhu Yuan
PUMA is a member of the "BH3-only" branch of the BCL-2 family. Our previous study suggests a therapeutic potential of PUMA in treating ovarian cancer, however, the action mechanism of PUMA remains elusive. In this work, we found that in PUMA adenovirus-infected A2780s ovarian cancer cells, exogenous PUMA was partially accumulated in the cytosol and mainly located to the mitochondria. We further showed that PUMA induces mitochondrial dysfunction-mediated apoptosis and ROS generation through functional BAX in a ROS generating enzyme- and caspase-independent manner irrespective of their p53 status, and results in activation of Nrf2/HO-1 pathway...
April 4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28415827/camptothecin-resistance-is-determined-by-the-regulation-of-topoisomerase-i-degradation-mediated-by-ubiquitin-proteasome-pathway
#3
Koji Ando, Ankur K Shah, Vibhu Sachdev, Benjamin P Kleinstiver, Julian Taylor-Parker, Moira M Welch, Yiheng Hu, Ravi Salgia, Forest M White, Jeffrey D Parvin, Al Ozonoff, Lucia E Rameh, J Keith Joung, Ajit K Bharti
Proteasomal degradation of topoisomerase I (topoI) is one of the most remarkable cellular phenomena observed in response to camptothecin (CPT). Importantly, the rate of topoI degradation is linked to CPT resistance. Formation of the topoI-DNA-CPT cleavable complex inhibits DNA re-ligation resulting in DNA-double strand break (DSB). The degradation of topoI marks the first step in the ubiquitin proteasome pathway (UPP) dependent DNA damage response (DDR). Here, we show that the Ku70/Ku80 heterodimer binds with topoI, and that the DNA-dependent protein kinase (DNA-PKcs) phosphorylates topoI on serine 10 (topoI-pS10), which is subsequently ubiquitinated by BRCA1...
March 18, 2017: Oncotarget
https://www.readbyqxmd.com/read/28415690/identification-of-dna-pkcs-as-a-primary-resistance-factor-of-tic10-in-hepatocellular-carcinoma-cells
#4
Long Cheng, Yuan-Yuan Liu, Pei-Hua Lu, Yi Peng, Qiang Yuan, Xin-Shi Gu, Yong Jin, Min-Bin Chen, Xu-Ming Bai
The current study tested the anti-hepatocellular carcinoma (HCC) cell activity of TIC10, a first-in-class small-molecule tumor necrosis (TNF)-related apoptosis-inducing ligand (TRAIL) inducer. TIC10 exerted potent anti-proliferative and pro-apoptotic actions in primary and established human HCC cells. TIC10 blocked Akt-Erk activation, leading to Foxo3a nuclear translocation, as well as TRAIL and death receptor-5 (DR5) transcription in HCC cells. We propose that DNA-PKcs is a major resistance factor of TIC10 possibly via inhibiting Foxo3a nuclear translocation...
March 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/28392410/differential-roles-of-pkc-isoforms-pkcs-in-gnrh-stimulation-of-mapk-phosphorylation-in-gonadotrope-derived-cells
#5
REVIEW
Shany Mugami, Masha Dobkin-Bekman, Liat Rahamim-Ben Navi, Zvi Naor
The role of protein kinase C (PKC) isoforms (PKCs) in GnRH-stimulated MAPK [ERK1/2, JNK1/2 and p38) phosphorylation was examined in gonadotrope derived cells. GnRH induced a protracted activation of ERK1/2 and a slower and more transient activation of JNK1/2 and p38MAPK. Gonadotropes express conventional PKCα and PKCβII, novel PKCδ, PKCε and PKCθ, and atypical PKC-ι/λ. The use of green fluorescent protein (GFP)-PKCs constructs revealed that GnRH induced rapid translocation of PKCα and PKCβII to the plasma membrane, followed by their redistribution to the cytosol...
April 6, 2017: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/28389298/stimulatory-and-inhibitory-effects-of-pkc-isozymes-are-mediated-by-serine-threonine-pkc-sites-of-the-cav2-3%C3%AE-1-subunits
#6
Senthilkumar Rajagopal, Brittney K Burton, Blanche L Fields, India O El, Ganesan L Kamatchi
Protein kinase C (PKC) isozymes modulate voltage-gated calcium (Cav) currents through Cav2.2 and Cav2.3 channels by targeting serine/threonine (Ser/Thr) phosphorylation sites of Cavα1 subunits. Stimulatory (Thr-422, Ser-2108 and Ser-2132) and inhibitory (Ser-425) sites were identified in the Cav2.2α1 subunits to PKCs βII and ε. In the current study, we investigated if the homologous sites of Cav2.3α1 subunits (stimulatory: Thr-365, Ser-1995 and Ser-2011; inhibitory: Ser-369) behaved in similar manner. Several Ala and Asp mutants were constructed in Cav2...
May 1, 2017: Archives of Biochemistry and Biophysics
https://www.readbyqxmd.com/read/28375174/protein-kinases-c-mediated-regulations-of-drug-transporter-activity-localization-and-expression
#7
REVIEW
Abdullah Mayati, Amélie Moreau, Marc Le Vée, Bruno Stieger, Claire Denizot, Yannick Parmentier, Olivier Fardel
Drug transporters are now recognized as major actors in pharmacokinetics, involved notably in drug-drug interactions and drug adverse effects. Factors that govern their activity, localization and expression are therefore important to consider. In the present review, the implications of protein kinases C (PKCs) in transporter regulations are summarized and discussed. Both solute carrier (SLC) and ATP-binding cassette (ABC) drug transporters can be regulated by PKCs-related signaling pathways. PKCs thus target activity, membrane localization and/or expression level of major influx and efflux drug transporters, in various normal and pathological types of cells and tissues, often in a PKC isoform-specific manner...
April 4, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28373118/synergism-between-pkc%C3%AE-regulators-hypericin-and-rottlerin-enhances-apoptosis-in-u87-mg-glioma-cells-after-light-stimulation
#8
Matus Misuth, Denis Horvath, Pavol Miskovsky, Veronika Huntosova
BACKGROUND: Gliomas belong to the most infiltrative types of tumors. Photodynamic therapy (PDT) can be applied to regulate glioma cell proliferation. The inhibitors of PKCs are very promising drugs that can mediate glioma cells apoptosis in PDT. Hypericin is one of PKCs regulators, and thanks to its physicochemical properties it can be used in PDT. Rottlerin is also considered to be the PKCδ inhibitor. Its implementation in PDT may significantly influence glioma cells response to PDT...
March 31, 2017: Photodiagnosis and Photodynamic Therapy
https://www.readbyqxmd.com/read/28369981/propofol-induces-excessive-vasodilation-of-aorta-rings-by-inhibiting-pkc%C3%AE-2-%C3%AE-in-spontaneously-hypertensive-rats
#9
Yan Wang, Quanhong Zhou, Bin Wu, Huixuan Zhou, Xiaoli Zhang, Wei Jiang, Li Wang, Aizhong Wang
BACKGROUND AND PURPOSE: Exaggerated hypotension following the administration of propofol is strongly predicted in patients with hypertension. Increased protein kinase Cs (PKCs) play a crucial role in regulating vascular tone. We studied whether propofol induces vasodilation by inhibiting increased PKC activity in spontaneously hypertensive rats (SHRs), and if so, whether contractile Ca(2+) -sensitization pathways and filamentous-globular (F/G) actin dynamics were involved. EXPERIMENTAL APPROACH: Denuded thoracic aortic rings from Wistar-Kyoto Rat (WKY) and SHR were prepared for functional studies...
March 28, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28362262/a-type-i-ifn-dependent-dna-damage-response-regulates-the-genetic-program-and-inflammasome-activation-in-macrophages
#10
Abigail J Morales, Javier A Carrero, Putzer J Hung, Anthony T Tubbs, Jared M Andrews, Brian T Edelson, Boris Calderon, Cynthia L Innes, Richard S Paules, Jacqueline E Payton, Barry P Sleckman
Macrophages produce genotoxic agents, such as reactive oxygen and nitrogen species, that kill invading pathogens. Here we show that these agents activate the DNA damage response (DDR) kinases ATM and DNA-PKcs through the generation of double stranded breaks (DSBs) in murine macrophage genomic DNA. In contrast to other cell types, initiation of this DDR depends on signaling from the type I interferon receptor. Once activated, ATM and DNA-PKcs regulate a genetic program with diverse immune functions and promote inflammasome activation and the production of IL-1β and IL-18...
March 31, 2017: ELife
https://www.readbyqxmd.com/read/28340172/repositioning-disulfiram-as-a-radiosensitizer-against-atypical-teratoid-rhabdoid-tumor
#11
Young Eun Lee, Seung Ah Choi, Pil Ae Kwack, Hak Jae Kim, Il Han Kim, Kyu-Chang Wang, Ji Hoon Phi, Ji Yeoun Lee, Sangjoon Chong, Sung-Hye Park, Kyung Duk Park, Do Won Hwang, Kyeung Min Joo, Seung-Ki Kim
Background.: Atypical teratoid/rhabdoid tumor (AT/RT) is one of the most common malignant brain tumors in infants. Although cancer stem cells of AT/RT express aldehyde dehydrogenase (ALDH), effective chemotherapies against AT/RT have not been established. Here, we examined radiosensitizing effects of disulfiram (DSF), an irreversible inhibitor of ALDH against AT/RT for a novel therapeutic method. Methods.: Patient-derived primary cultured AT/RT cells (SNU.AT/RT-5 and SNU...
March 17, 2017: Neuro-oncology
https://www.readbyqxmd.com/read/28331416/dna-pk-inhibition-by-nu7441-enhances-chemosensitivity-to-topoisomerase-inhibitor-in-non-small-cell-lung-carcinoma-cells-by-blocking-dna-damage-repair
#12
Masaaki Yanai, Haruhiko Makino, Bingqiong Ping, Kenichi Takeda, Natsumi Tanaka, Tomohiro Sakamoto, Kosuke Yamaguchi, Masahiro Kodani, Akira Yamasaki, Tadashi Igishi, Eiji Shimizu
BACKGROUND: DNA double-strand breaks (DSBs) are the most cytotoxic form of DNA damage and are induced by ionizing radiation and specific chemotherapeutic agents, such as topoisomerase inhibitors. Cancer cells acquire resistance to such therapies by repairing DNA DSBs. A major pathway for the repair of DNA DSBs is non-homologous end-joining (NHEJ), which requires DNA-dependent protein kinase (DNA-PK) activity. In this study, we investigated the effect of NU7441, a synthetic small-molecule compound, as a specific inhibitor of DNA-PK on the chemosensitization of non-small cell lung carcinoma (NSCLC) A549 cells...
March 2017: Yonago Acta Medica
https://www.readbyqxmd.com/read/28329681/sirt6-promotes-dna-end-joining-in-ipscs-derived-from-old-mice
#13
Wen Chen, Nana Liu, Hongxia Zhang, Haiping Zhang, Jing Qiao, Wenwen Jia, Songcheng Zhu, Zhiyong Mao, Jiuhong Kang
Induced pluripotent stem cells (iPSCs) have great potential for treating age-related diseases, but the genome integrity of iPSCs is critically important. Here, we demonstrate that non-homologous end joining (NHEJ), rather than homologous recombination (HR), is less efficient in iPSCs from old mice than young mice. We further find that Sirt6 is downregulated in iPSCs from old mice. Sirt6 directly binds to Ku80 and facilitates the Ku80/DNA-PKcs interaction, thus promoting DNA-PKcs phosphorylation at residue S2056, leading to efficient NHEJ...
March 21, 2017: Cell Reports
https://www.readbyqxmd.com/read/28328082/microrna-488-3p-sensitizes-malignant-melanoma-cells-to-cisplatin-by-targeting-prkdc
#14
Ning Li, Yue Ma, Li Ma, Yu Guan, Liang Ma, Daping Yang
Deregulation of microRNAs (miRNAs) has been implicated in drug resistance in various types of cancers, including malignant melanoma (MM). MiR-488-3p has been reported as a tumor suppressor in several cancers. However, the exact expression patterns of miR-488-3p and the precise molecular mechanisms underlying its role in MM remain largely unknown and require further investigation. In this study, we demonstrated that miR-488-3p is significantly down regulated in MM clinical specimens and cell lines. Ectopic expression of miR-488-3p resulted in markedly increased drug sensitivity of MM cells in vitro and in vivo...
March 22, 2017: Cell Biology International
https://www.readbyqxmd.com/read/28315428/p53-modulates-the-effect-of-ribosomal-protein-s6-kinase1-s6k1-on-cisplatin-toxicity-in-chronic-myeloid-leukemia-cells
#15
Ling-Yi Xiao, Wai-Ming Kan
Chronic myeloid leukemia (CML) is characterized by the expression of the oncoprotein, BCR-ABL. BCR-ABL inhibitors revolutionized CML chemotherapy while blast crisis (BC) CML patients are less responsive. Since suppression of ribosomal protein S6 kinase1 (S6K1) phosphorylation reverses the resistance to BCR-ABL inhibitor in CML cells and S6K1 inhibitors augment cisplatin toxicity in lung cancer cells, we speculated that combination of S6K1 inhibitor and cisplatin may be beneficial for eliminating BC CML cells...
May 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/28300555/inhibiting-dna-pkcs-radiosensitizes-human-osteosarcoma-cells
#16
Tewodros Mamo, Ann C Mladek, Kris L Shogren, Carl Gustafson, Shiv K Gupta, Scott M Riester, Avudaiappan Maran, Mario Galindo, Andre J van Wijnen, Jann N Sarkaria, Michael J Yaszemski
Osteosarcoma survival rate has not improved over the past three decades, and the debilitating side effects of the surgical treatment suggest the need for alternative local control approaches. Radiotherapy is largely ineffective in osteosarcoma, indicating a potential role for radiosensitizers. Blocking DNA repair, particularly by inhibiting the catalytic subunit of DNA-dependent protein kinase (DNA-PKCS), is an attractive option for the radiosensitization of osteosarcoma. In this study, the expression of DNA-PKCS in osteosarcoma tissue specimens and cell lines was examined...
April 29, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28270495/the-checkpoint-kinase-1-inhibitor-prexasertib-induces-regression-of-preclinical-models-of-human-neuroblastoma
#17
Caitlin D Lowery, Alle B VanWye, Michele Dowless, Wayne Blosser, Beverly L Falcon, Julie Stewart, Jennifer Stephens, Richard P Beckmann, Aimee Bence Lin, Louis F Stancato
PURPOSE: Checkpoint kinase 1 (CHK1) is a key regulator of the DNA damage response and a mediator of replication stress through modulation of replication fork licensing and activation of S and G2/M cell cycle checkpoints. We evaluated prexasertib (LY2606368), a small molecule CHK1 inhibitor currently in clinical testing, in multiple preclinical models of pediatric cancer. Following an initial assessment of prexasertib activity, this study focused on preclinical models of neuroblastoma...
March 7, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28258841/stimulation-of-lactate-receptor-hcar1-affects-cellular-dna-repair-capacity
#18
Waldemar Wagner, Katarzyna D Kania, Wojciech M Ciszewski
Numerous G-protein coupled receptors have been reported to enhance cancer cell survival and resistance to clinically used chemotherapeutics. Recently, hydroxycarboxylic acid receptor 1 (HCAR1) was shown to drive lactate-dependent enhancement of cell survival and metastasis in pancreatic and breast cancers. Furthermore, our previous study confirmed the involvement of HCAR1 in lactate-related enhancement of DNA repair in cervical cancer cells. In the present study, we examined the possible mechanisms of HCAR1-mediated enhancement of DNA repair capacity...
February 20, 2017: DNA Repair
https://www.readbyqxmd.com/read/28254786/clinical-impact-of-tumor-dna-repair-expression-and-t-cell-infiltration-in-breast-cancers
#19
Andrew R Green, Mohammed A Aleskandarany, Reem Ali, Eleanor Grace Hodgson, Suha Atabani, Karen De Souza, Emad Rakha, Ian O Ellis, Srinivasan Madhusudan
Impaired DNA repair drives mutagenicity, which increases neoantigen load and immunogenicity. We investigated the expression of proteins involved in the DNA damage response (ATM, Chk2), double-strand break repair (BRCA1, BLM, WRN, RECQL4, RECQL5, TOPO2A, DNA-PKcs, Ku70/Ku80), nucleotide excision repair (ERCC1), base excision repair (XRCC1, pol β, FEN1, PARP1), and immune responses (CD8, PD-1, PD-L1, FOXP3) in 1269 breast cancers and validated our findings in an independent estrogen receptor (ER)- cohort (n = 279)...
March 2, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/28224663/loss-of-mlh1-sensitizes-colon-cancer-cells-to-dna-pkcs-inhibitor-ku60648
#20
Inga Hinrichsen, Anne Ackermann, Tonja Düding, Annika Graband, Natalie Filmann, Guido Plotz, Stefan Zeuzem, Angela Brieger
Germline mutations of MLH1 are responsible for tumor generation in nearly 50% of patients with Lynch Syndrome, and around 15% of sporadic colorectal cancers show MLH1-deficiency due to promotor hypermethylation. Although these tumors are of lower aggressiveness the benefit for these patients from standard chemotherapy is still under discussion. Recently, it was shown that the sensitivity to the DNA-PKcs inhibitor KU60648 is linked to loss of the MMR protein MSH3. However, loss of MSH3 is rather secondary, as a consequence of MMR-deficiency, and frequently detectable in MLH1-deficient tumors...
February 22, 2017: Molecular Carcinogenesis
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