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Autophagy and radiation resistance

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https://www.readbyqxmd.com/read/28282258/wnk1-is-an-unexpected-autophagy-inhibitor
#1
Sachith Gallolu Kankanamalage, A-Young Lee, Chonlarat Wichaidit, Andres Lorente-Rodriguez, Akansha M Shah, Steve Stippec, Angelique W Whitehurst, Melanie H Cobb
Autophagy is a cellular degradation pathway that is essential to maintain cellular physiology, and deregulation of autophagy leads to multiple diseases in humans. In a recent study, we discovered that the protein kinase WNK1 (WNK lysine deficient protein kinase 1) is an inhibitor of autophagy. The loss of WNK1 increases both basal and starvation-induced autophagy. In addition, the depletion of WNK1 increases the activation of the class III phosphatidylinositol 3-kinase (PtdIns3K) complex, which is required to induce autophagy...
February 15, 2017: Autophagy
https://www.readbyqxmd.com/read/28260023/silencing-bmi1-radiosensitizes-human-breast-cancer-cells-by-inducing-dna-damage-and-autophagy
#2
James Griffith, Daniel Andrade, Meghna Mehta, William Berry, Doris M Benbrook, Natarajan Aravindan, Terence S Herman, Rajagopal Ramesh, Anupama Munshi
Overexpression of BMI1 in human cancer cells, a member of the polycomb group of repressive complexes, correlates with advanced stage of disease, aggressive clinico-pathological behavior, poor prognosis, and resistance to radiation and chemotherapy. Studies have shown that experimental reduction of BMI1 protein level in tumor cells results in inhibition of cell proliferation, induction of apoptosis and/or senescence, and increased susceptibility to cytotoxic agents and radiation therapy. Although a role for BMI1 in cancer progression and its importance as a molecular target for cancer therapy has been established, information on the impact of silencing BMI1 in triple-negative breast cancer (TNBC) and its consequence on radiotherapy have not been well studied...
February 28, 2017: Oncology Reports
https://www.readbyqxmd.com/read/28225086/uvrag-deficiency-exacerbates-doxorubicin-induced-cardiotoxicity
#3
Lin An, Xiao-Wen Hu, Shasha Zhang, Xiaowen Hu, Zongpei Song, Amber Naz, Zhenguo Zi, Jian Wu, Can Li, Yunzeng Zou, Lin He, Hongxin Zhu
Doxorubicin (DOX) is an effective chemotherapeutic drug in the treatment of various types of cancers. However, its clinical application has been largely limited by potential development of cardiotoxicity. Previously we have shown that ultra-violet radiation resistance-associated gene (UVRAG), an autophagy-related protein, is essential for the maintenance of autophagic flux in the heart under physiological conditions. Here, we sought to determine the role of UVRAG-mediated autophagy in DOX-induced cardiotoxicity...
February 22, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28208579/role-of-autophagy-and-apoptosis-in-non-small-cell-lung-cancer
#4
REVIEW
Guangbo Liu, Fen Pei, Fengqing Yang, Lingxiao Li, Amit Dipak Amin, Songnian Liu, J Ross Buchan, William C Cho
Non-small-cell lung cancer (NSCLC) constitutes 85% of all lung cancers, and is the leading cause of cancer-related death worldwide. The poor prognosis and resistance to both radiation and chemotherapy warrant further investigation into the molecular mechanisms of NSCLC and the development of new, more efficacious therapeutics. The processes of autophagy and apoptosis, which induce degradation of proteins and organelles or cell death upon cellular stress, are crucial in the pathophysiology of NSCLC. The close interplay between autophagy and apoptosis through shared signaling pathways complicates our understanding of how NSCLC pathophysiology is regulated...
February 10, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28104298/kr%C3%A3-pple-like-factor-10-regulates-radio-sensitivity-of-pancreatic-cancer-via-uv-radiation-resistance-associated-gene
#5
Vincent Hung-Shu Chang, Yi-Chih Tsai, Ya-Li Tsai, Shu-Ling Peng, Su-Liang Chen, Tsung Ming Chang, Winston Chun-Yuan Yu, Hui-Ju Ch'ang
BACKGROUND AND PURPOSE: Krüpple-like factor 10 (Klf10), an early response gene of TGFβ, was reported to be a prognostic biomarker for pancreatic cancer survival. The role of Klf10 in predicting tumor response to cancer treatment is unknown. MATERIALS AND METHODS: Genetically manipulated MiaPaCa and Panc-1 cells were established to evaluate clonogenic survival, autophagy, apoptosis and DNA repair after radiation. The interaction between Klf10 and UV radiation resistance-associated gene (UVRAG) was demonstrated by ChiP-PCR and luciferase reporter assay...
January 16, 2017: Radiotherapy and Oncology: Journal of the European Society for Therapeutic Radiology and Oncology
https://www.readbyqxmd.com/read/28010924/upregulation-of-nrf2-through-autophagy-erk-1-2-ameliorates-ionizing-radiation-induced-cell-death-of-human-osteosarcoma-u-2-os
#6
Ni Chen, Rui Zhang, Teruaki Konishi, Jun Wang
The antioxidative response mediated by transcription factor NRF2 is thought to be a pivotal cellular defense system against various extrinsic stresses. It has been reported that activation of the NRF2 pathway confers cells with resistance to ionizing radiation-induced damage. However, the underlying mechanism remains largely unknown. In the current research, it was found that α-particle radiation has the ability to stimulate NRF2 expression in human osteosarcoma U-2 OS cells. Knockdown of cellular NRF2 level by shRNA-mediated gene silencing decreased the survival rate, increased the micronucleus formation rate and apoptosis rate in irradiated cells...
January 2017: Mutation Research
https://www.readbyqxmd.com/read/27994676/pre-clinical-evaluation-of-a-novel-class-of-anti-cancer-agents-the-pyrrolo-1-5-benzoxazepines
#7
REVIEW
L M Greene, S Butini, G Campiani, D C Williams, D M Zisterer
Microtubules are currently ranked one of the most validated targets for chemotherapy; with clinical use of microtubule targeting agents (MTAs) extending beyond half a century. Recent research has focused on the development of novel MTAs to combat drug resistance and drug associated toxicities. Of particular interest are compounds structurally different to those currently used within the clinic. The pyrrolo-1, 5-benzoxazepines (PBOXs) are a structurally distinct novel group of anti-cancer agents, some of which target tubulin...
2016: Journal of Cancer
https://www.readbyqxmd.com/read/27929538/downregulation-of-aspp2-improves-hepatocellular-carcinoma-cells-survival-via-promoting-becn1-dependent-autophagy-initiation
#8
Rui Chen, Hao Wang, Beibei Liang, Guoke Liu, Min Tang, Rongjie Jia, Xiaoyu Fan, Wei Jing, Xuyu Zhou, Huajing Wang, Yang Yang, Huafeng Wei, Bohua Li, Jian Zhao
Autophagy is an important catabolic process, which sustains intracellular homeostasis and lengthens cell survival under stress. Here we identify the ankyrin-repeat-containing, SH3-domain-containing, and proline-rich region-containing protein 2 (ASPP2), a haploinsufficient tumor suppressor, as a molecular regulator of starvation-induced autophagy in hepatocellular carcinoma (HCC). ASPP2 expression is associated with an autophagic response upon nutrient deprivation and downregulation of ASPP2 facilitates autophagic flux, whereas overexpression of ASPP2 blocks this starvation-induced autophagy in HCC cells...
December 8, 2016: Cell Death & Disease
https://www.readbyqxmd.com/read/27911840/multistep-regulation-of-autophagy-by-wnk1
#9
Sachith Gallolu Kankanamalage, A-Young Lee, Chonlarat Wichaidit, Andres Lorente-Rodriguez, Akansha M Shah, Steve Stippec, Angelique W Whitehurst, Melanie H Cobb
The with-no-lysine (K) (WNK) kinases are an atypical family of protein kinases that regulate ion transport across cell membranes. Mutations that result in their overexpression cause hypertension-related disorders in humans. Of the four mammalian WNKs, only WNK1 is expressed throughout the body. We report that WNK1 inhibits autophagy, an intracellular degradation pathway implicated in several human diseases. Using small-interfering RNA-mediated WNK1 knockdown, we show autophagosome formation and autophagic flux are accelerated...
December 13, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27900012/ubenimex-enhances-the-radiosensitivity-of-renal-cell-carcinoma-cells-by-inducing-autophagic-cell-death
#10
Shuai Liu, Xiaoqing Wang, Jiaju Lu, Liping Han, Yongfei Zhang, Zheng Liu, Sentai Ding, Zhao Liu, Dongbin Bi, Zhihong Niu
Renal cell carcinoma (RCC) is resistant to standard radiotherapy. Ubenimex, an aminopeptidase N inhibitor, is widely used as an adjunct therapy after surgery to enhance the function of immunocompetent cells and confer antitumor effects. Our previous study demonstrated that ubenimex induces autophagic cell death in RCC cells. Recently, the molecular mechanism of autophagy induction has been associated with radiosensitivity in RCC cells. In the present study, the ability of ubenimex to enhance RCC cell sensitivity to radiation via the induction of autophagic cell death was determined, and the mechanism of action of this effect was investigated...
November 2016: Oncology Letters
https://www.readbyqxmd.com/read/27899501/unraveling-fungal-radiation-resistance-regulatory-networks-through-the-genome-wide-transcriptome-and-genetic-analyses-of-cryptococcus-neoformans
#11
Kwang-Woo Jung, Dong-Hoon Yang, Min-Kyu Kim, Ho Seong Seo, Sangyong Lim, Yong-Sun Bahn
The basidiomycetous fungus Cryptococcus neoformans has been known to be highly radiation resistant and has been found in fatal radioactive environments such as the damaged nuclear reactor at Chernobyl. To elucidate the mechanisms underlying the radiation resistance phenotype of C. neoformans, we identified genes affected by gamma radiation through genome-wide transcriptome analysis and characterized their functions. We found that genes involved in DNA damage repair systems were upregulated in response to gamma radiation...
November 29, 2016: MBio
https://www.readbyqxmd.com/read/27845767/activating-autophagy-to-potentiate-immunogenic-chemotherapy-and-radiation-therapy
#12
REVIEW
Lorenzo Galluzzi, José Manuel Bravo-San Pedro, Sandra Demaria, Silvia Chiara Formenti, Guido Kroemer
Autophagy is fundamental to the maintenance of intracellular homeostasis in virtually all human cells. Accordingly, defective autophagy predisposes healthy cells to undergoing malignant transformation. By contrast, malignant cells are able to harness autophagy to thrive, despite adverse microenvironmental conditions, and to resist therapeutic challenges. Thus, inhibition of autophagy has been proposed as a strategy to kill cancer cells or sensitize them to therapy; however, autophagy is also critical for optimal immune function, and mediates cell-extrinsic homeostatic effects owing to its central role in danger signalling by neoplastic cells responding to immunogenic chemotherapy and/or radiation therapy...
April 2017: Nature Reviews. Clinical Oncology
https://www.readbyqxmd.com/read/27845161/downregulation-of-autophagy-gene-expression-in-endometria-from-women-with-polycystic-ovary-syndrome
#13
Mirjana Sumarac-Dumanovic, Milica Apostolovic, Kristina Janjetovic, Danka Jeremic, Dusan Popadic, Aleksandar Ljubic, Jelena Micic, Jelena Dukanac-Stamenkovic, Aleksandra Tubic, Darko Stevanovic, Dragan Micic, Vladimir Trajkovic
Autophagy, a process of controlled cellular self-digestion, could be involved in cyclic remodeling of the human endometrium. We investigated endometrial mRNA expression of 23 autophagy-related (ATG) genes and transcription factors in healthy controls (n = 12) and anovulatory polycystic ovary syndrome (PCOS) patients (n = 24), as well as in their subgroup (n = 12) before and after metformin treatment. The mRNA levels of transcription factor forkhead box protein O1 (FOXO1) and several molecules involved in autophagosome formation (ATG13, RB1-inducible coiled-coil 1), autophagosome nucleation (ATG14, beclin 1, SH3-domain GRB2-like endophilin B1), autophagosome elongation (ATG3, ATG5, γ-aminobutyric acid receptor-associated protein - GABARAP), and delivery of ubiquitinated proteins to autophagosomes (sequestosome 1), were significantly reduced in anovulatory PCOS compared to healthy endometrium...
January 15, 2017: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/27775833/targeting-deubiquitinating-enzymes-in-glioblastoma-multiforme-expectations-and-challenges
#14
Wei-Lin Jin, Xiao-Yuan Mao, Guan-Zhong Qiu
Glioblastoma (GBM) is regarded as the most common primary intracranial neoplasm. Despite standard treatment with tumor resection and radiochemotherapy, the outcome remains gloomy. It is evident that a combination of oncogenic gain of function and tumor-suppressive loss of function has been attributed to glioma initiation and progression. The ubiquitin-proteasome system is a well-orchestrated system that controls the fate of most proteins by striking a dynamic balance between ubiquitination and deubiquitination of substrates, having a profound influence on the modulation of oncoproteins, tumor suppressors, and cellular signaling pathways...
October 24, 2016: Medicinal Research Reviews
https://www.readbyqxmd.com/read/27757033/silver-nanoparticles-outperform-gold-nanoparticles-in-radiosensitizing-u251-cells-in-vitro-and-in-an-intracranial-mouse-model-of-glioma
#15
Peidang Liu, Haizhen Jin, Zhirui Guo, Jun Ma, Jing Zhao, Dongdong Li, Hao Wu, Ning Gu
Radiotherapy performs an important function in the treatment of cancer, but resistance of tumor cells to radiation still remains a serious concern. More research on more effective radiosensitizers is urgently needed to overcome such resistance and thereby improve the treatment outcome. The goal of this study was to evaluate and compare the radiosensitizing efficacies of gold nanoparticles (AuNPs) and silver nanoparticles (AgNPs) on glioma at clinically relevant megavoltage energies. Both AuNPs and AgNPs potentiated the in vitro and in vivo antiglioma effects of radiation...
2016: International Journal of Nanomedicine
https://www.readbyqxmd.com/read/27693581/fasting-boosts-sensitivity-of-human-skin-melanoma-to-cisplatin-induced-cell-death
#16
Fernanda Antunes, Marco Corazzari, Gustavo Pereira, Gian Maria Fimia, Mauro Piacentini, Soraya Smaili
Melanoma is one of leading cause of tumor death worldwide. Anti-cancer strategy includes combination of different chemo-therapeutic agents as well as radiation; however these treatments have limited efficacy and induce significant toxic effects on healthy cells. One of most promising novel therapeutic approach to cancer therapy is the combination of anti-cancer drugs with calorie restriction. Here we investigated the effect Cisplatin (CDDP), one of the most potent chemotherapeutic agent used to treat tumors, in association with fasting in wild type and mutated BRAF(V600E) melanoma cell lines...
March 25, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27507051/bh3-mimetic-obatoclax-gx15-070-mediates-mitochondrial-stress-predominantly-via-mcl-1-inhibition-and-induces-autophagy-dependent-necroptosis-in-human-oral-cancer-cells
#17
Prasad Sulkshane, Tanuja Teni
We have previously reported overexpression of antiapoptotic MCL-1 protein in human oral cancers and its association with therapy resistance and poor prognosis, implying it to be a potential therapeutic target. Hence, we investigated the efficacy and mechanism of action of Obatoclax, a BH3 mimetic pan BCL-2 inhibitor in human oral cancer cell lines. All cell lines exhibited high sensitivity to Obatoclax with complete clonogenic inhibition at 200-400 nM concentration which correlated with their MCL-1 expression...
August 5, 2016: Oncotarget
https://www.readbyqxmd.com/read/27478804/carcinoembryonic-antigen-expression-and-resistance-to-radiation-and-5-fluorouracil-induced-apoptosis-and-autophagy
#18
Ebrahim Eftekhar, Hajar Jaberie, Fakhraddin Naghibalhossaini
Understanding the mechanism of tumor resistance is critical for cancer therapy. In this study, we investigated the effect of carcinoembryonic antigen (CEA) overexpression on UV-and 5-fluorouracil (5-FU)-induced apoptosis and autophagy in colorectal cancer cells. We used histone deacetylase (HDAC) inhibitor, NaB and DNA demethylating agent, 5-azacytidine (5-AZA) to induce CEA expression in HT29/219 and SW742 colorectal cancer cell lines. MTT assay was used to measure IC50 value of the cells exposed to graded concentrations of 5- FU with either 0...
2016: International Journal of Molecular and Cellular Medicine
https://www.readbyqxmd.com/read/27414780/-nutrient-restriction-in-combinatory-therapy-of-tumors
#19
REVIEW
V V Senichkin, G S Kopeina, A V Zamaraev, I N Lavrik, B D Zhivotovsky
The main objective of anticancer treatment is the elimination of degenerated cells by the induction of programmed cell death. Various chemotherapy drugs and radiation are able to activate cell death mechanisms in tumors. However, unfortunately, monotherapy will always be insufficiently effective because of the variety and virulence of tumors, as well as their ability to develop resistance to drugs. Moreover, monotherapy might constrain many negative side effects. Therefore, the combination of different approaches and/or drugs will increase the efficiency of treatment...
May 2016: Molekuliarnaia Biologiia
https://www.readbyqxmd.com/read/27380135/repression-of-the-autophagic-response-sensitises-lung-cancer-cells-to-radiation-and-chemotherapy
#20
Ilias V Karagounis, Dimitra Kalamida, Achilleas Mitrakas, Stamatia Pouliliou, Maria V Liousia, Alexandra Giatromanolaki, Michael I Koukourakis
BACKGROUND: The cellular autophagic response to radiation is complex. Various cells and tissues respond differentially to radiation, depending on both the dose of exposure and the time post irradiation. In the current study, we determined the autophagosomal and lysosomal response to radiation in lung cancer cell lines by evaluating the expression of the associated proteins, as well as the effect of relevant gene silencing in radio and chemosensitisation. Furthermore, tumour sensitisation was evaluated in in vivo autophagic gene silencing model after irradiation...
July 26, 2016: British Journal of Cancer
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