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Autophagy leukemia

Anja Göder, Nisintha Mahendrarajah, Oliver H Krämer
Autophagy is a lysosome-dependent, intracellular pathway for the recycling of cellular components. It plays a pivotal role in both cancer development and the response to chemotherapy. Here we describe how autophagy can be monitored in living cells by flow cytometry using the cationic amphiphilic tracer dye Cyto-ID(®) Green. The detection of autophagy induction in the human leukemia cell line K562 after the treatment with the HDAC class I inhibitor MS-275 serves as an example for this approach.
2017: Methods in Molecular Biology
Xiaoli Wu, Xuefeng Feng, Xiaoqing Zhao, Futian Ma, Na Liu, Hongming Guo, Chaonan Li, Huan Du, Baoxi Zhang
BACKGROUND/AIMS: Acute and chronic leukemia are severe malignant cancers worldwide, and can occur in pediatric patients. Since bone marrow cell transplantation is seriously limited by the availability of the immune-paired donor sources, the therapy for pediatric leukemia (PL) remains challenging. Autophagy is essential for the regulation of cell survival in the harsh environment. However, the role of autophagy in the survival of PL cells under the oxidative stress, e.g. chemotherapy, remain ill-defined...
October 17, 2016: Cellular Physiology and Biochemistry
Zhen-Hua Chen, Wen-Tao Wang, Wei Huang, Ke Fang, Yu-Meng Sun, Shu-Rong Liu, Xue-Qun Luo, Yue-Qin Chen
Increasing evidence has indicated that long noncoding RNAs (lncRNAs) are of great importance in different cell contexts. However, only a very small number of lncRNAs have been experimentally validated and functionally annotated during human hematopoiesis. Here, we report an lncRNA, HOTAIRM1, which is associated with myeloid differentiation and has pivotal roles in the degradation of oncoprotein PML-RARA and in myeloid cell differentiation by regulating autophagy pathways. We first revealed that HOTAIRM1 has different variants that are expressed at different levels in cells and that the expression pattern of HOTAIRM1 is closely related to that of the PML-RARA oncoprotein in acute promyelocytic leukemia (APL) patients...
October 14, 2016: Cell Death and Differentiation
Min Huang, Jacqueline S Garcia, Daniel Thomas, Li Zhu, Le Xuan Truong Nguyen, Steven M Chan, Ravindra Majeti, Bruno C Medeiros, Beverly S Mitchell
The mechanisms underlying activation of the BET pathway in AML cells remain poorly understood. We have discovered that autophagy is activated in acute leukemia cells expressing mutant nucleophosmin 1 (NPMc+) or MLL-fusion proteins. Autophagy activation results in the degradation of NPM1 and HEXIM1, two negative regulators of BET pathway activation. Inhibition of autophagy with pharmacologic inhibitors or through knocking down autophagy-related gene 5 (Atg5) expression increases the expression of both NPM1 and HEXIM1...
October 6, 2016: Oncotarget
Hao Zhang, Weipeng Su, Zhixiong Ying, Yueping Chen, Le Zhou, Yue Li, Jingfei Zhang, Lili Zhang, Tian Wang
PURPOSE: The objective of the present study was to test the hypothesis that N-acetylcysteine (NAC) may play beneficial roles against intrauterine growth retardation (IUGR)-induced hepatic damage in suckling piglets. METHODS: Fourteen IUGR and seven normal birth weight (NBW) neonatal male piglets were selected. Piglets were weaned at 7 days of postnatal age and fed the control formula milk (NBW-CON and IUGR-CON groups) or the control formula milk supplemented with 1...
October 8, 2016: European Journal of Nutrition
Mohammad Amin Moosavi, Maryam Sharifi, Soroush Moasses Ghafary, Zahra Mohammadalipour, Alireza Khataee, Marveh Rahmati, Sadaf Hajjaran, Marek J Łos, Thomas Klonisch, Saeid Ghavami
In this study, we used nitrogen-doped titanium dioxide (N-TiO2) NPs in conjugation with visible light, and show that both reactive oxygen species (ROS) and autophagy are induced by this novel NP-based photodynamic therapy (PDT) system. While well-dispersed N-TiO2 NPs (≤100 μg/ml) were inert, their photo-activation with visible light led to ROS-mediated autophagy in leukemia K562 cells and normal peripheral lymphocytes, and this increased in parallel with increasing NP concentrations and light doses. At a constant light energy (12 J/cm(2)), increasing N-TiO2 NP concentrations increased ROS levels to trigger autophagy-dependent megakaryocytic terminal differentiation in K562 cells...
October 4, 2016: Scientific Reports
Wiem Chaabane, Malin Lindqvist Appell
Thiopurines (azathioprine, 6-mercaptopurine and 6-thioguanine) are a class of genotoxic drugs extensively used in the treatment of various illnesses including leukemia. Their underlying molecular mechanism of action involves the activation of apoptosis and autophagy but remains widely unclear. Here we present evidence that autophagy induction by thiopurines is a survival mechanism that antagonizes apoptosis and is involved in degrading damaged mitochondria through mitophagy. On the other hand, apoptosis is the main cell death mechanism by thiopurines as its inhibition prohibited cell death...
September 28, 2016: Oncotarget
Lorenzo Galluzzi
At odds with its nuclear counterpart, extranuclear promyelocytic leukemia constitutively inhibits autophagy, hence limiting cancer progression. These data raise the interesting possibility that some tumor suppressors have become specialized to operate at multiple subcellular compartments for counteracting different aspects of the oncogenic process.
September 20, 2016: Trends in Cell Biology
Pei Zhou, Yu-Zhen Tan, Hai-Jie Wang, Ting Li, Tao He, Ying Yu, Jian Zhang, Dan Zhang
Clearance of the apoptotic cells by phagocytes plays pivotal roles in maintenance of tissue homeostasis, promotion of immunological tolerance and anti-inflammatory response. Recent studies show that autophagy is involved in phagocytosis of the apoptotic cells. However, contribution of autophagy to phagocytosis of the apoptotic cells by macrophages is not clearly defined. Here, we assessed cytoprotective effect of autophagy on clearance of the apoptotic cells. Apoptosis of murine splenic lymphocytes and human T-cell leukemia cells was induced with cyclophosphamide...
September 20, 2016: Experimental Cell Research
Ying Lu, Ling-Ling Liu, Shou-Sheng Liu, Zhi-Gang Fang, Yong Zou, Xu-Bin Deng, Zi-Jie Long, Quentin Liu, Dong-Jun Lin
BACKGROUND: Chronic myelogenous leukemia (CML) is a hematological stem cell disorder. Tyrosine kinase inhibitors (TKIs) are the standard treatments for CML, but a number of patients fail to respond effectively due to gene mutations. Celecoxib, a cyclooxygenase-2 (COX-2) inhibitor, has been shown to have anti-tumor effect on solid tumor whereas the anti-CML effect and its underlying mechanism have not been completely elucidated. METHODS: The cytotoxic effects of celecoxib and/or imatinib were evaluated by MTT assay...
2016: Journal of Translational Medicine
Si-Jia He, Li-Ping Shu, Zhi-Wei Zhou, Tianxin Yang, Wei Duan, Xueji Zhang, Zhi-Xu He, Shu-Feng Zhou
Leukemia is a common malignancy of blood cells with poor prognosis in many patients. Aurora kinases, a family of serine/threonine kinases, play a key role in regulating cell division and mitosis and are linked to tumorigenesis, metastasis, and poor prognosis in many human cancers including leukemia and lymphoma. Danusertib (Danu) is a pan-inhibitor of Aurora kinases with few data available in leukemia therapy. This study aimed to identify new molecular targets for Aurora kinase inhibition in human leukemia cells using quantitative proteomic analysis followed by verification experiments...
September 6, 2016: Cancer Letters
Qiang Liu, Longgui Chen, Jennifer M Atkinson, David F Claxton, Hong-Gang Wang
Acute myeloid leukemia (AML) is a hierarchical hematopoietic malignancy originating from leukemic stem cells (LSCs). Autophagy is a lysosomal degradation pathway that is hypothesized to be important for the maintenance of AML as well as contribute to chemotherapy response. Here we employ a mouse model of AML expressing the fusion oncogene MLL-AF9 and explore the effects of Atg5 deletion, a key autophagy protein, on the malignant transformation and progression of AML. Consistent with a transient decrease in colony-forming potential in vitro, the in vivo deletion of Atg5 in MLL-AF9-transduced bone marrow cells during primary transplantation prolonged the survival of recipient mice, suggesting that autophagy has a role in MLL-AF9-driven leukemia initiation...
2016: Cell Death & Disease
Wen-Han Chang, Huey-Lan Huang, Wei-Pang Huang, Chien-Chih Chen, Yu-Jen Chen
Armillaridin (AM) is an aromatic ester compound isolated from Armillaria mellea. Treatment with AM markedly reduced the viability of human chronic myelogenous leukemia K562, chronic erythroleukemia HEL 92.1.7, and acute monoblastic leukemia U937 cells, but not normal human monocytes, in a dose- and time-dependent manner. Treatment of K562 cells with AM caused changes characteristic of autophagy. Only a small amount of AM-treated K562 cells exhibited apoptosis. By contrast, AM treatment resulted in extensive apoptotic features in U937 and HEL 92...
September 3, 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Padmaja Gade, Amy S Kimball, Angela C DiNardo, Priyamvada Gangwal, Douglas D Ross, H Scott Boswell, Susan K Keay, Dhananjaya V Kalvakolanu
Expression of DAPK1, a critical regulator of autophagy and apoptosis, is lost in a wide variety of tumors, although the mechanisms are unclear. A transcription factor complex consisting of ATF6 (an endoplasmic reticulum-resident factor) and C/EBP-β is required for the IFN-γ-induced expression of DAPK1 IFN-γ-induced proteolytic processing of ATF6 and phosphorylation of C/EBP-β are obligatory for the formation of this transcriptional complex. We report that defects in this pathway fail to control growth of chronic lymphocytic leukemia (CLL)...
October 14, 2016: Journal of Biological Chemistry
Sujuan Guo, Kevin J Pridham, Zhi Sheng
Autophagy is a catabolic process whereby cellular components are degraded to fuel cells for longer survival during stress. Hence, autophagy plays a vital role in determining cell fate and is central for homeostasis and pathogenesis of many human diseases including chronic myeloid leukemia (CML). It has been well established that autophagy is important for the leukemogenesis as well as drug resistance in CML. Thus, autophagy is an intriguing therapeutic target. However, current approaches that detect autophagy lack reliability and often fail to provide quantitative measurements...
2016: Methods in Molecular Biology
Antoine Millet, Magali Plaisant, Cyril Ronco, Michaël Cerezo, Patricia Abbe, Emilie Jaune, Elisa Cavazza, Stéphane Rocchi, Rachid Benhida
Cancer is the second cause of deaths worldwide and is forecasted to affect more that 22 million people in 2020. Despite dramatic improvement in its care over the last two decades, the treatment of resistant forms of cancer is still an unmet challenge. Thus, innovative and efficient treatments are still needed. In this context, we report herein the synthesis and the evaluation of a new class of bioactive molecules belonging to the N-(4-(3-aminophenyl(thiazol-2-yl)acetamide family. Structure-activity relationships could be driven and resulted in the discovery of lead compound 6b...
September 22, 2016: Journal of Medicinal Chemistry
S Ganesan, A A Alex, E Chendamarai, N Balasundaram, H K Palani, S David, U Kulkarni, M Aiyaz, R Mugasimangalam, A Korula, A Abraham, A Srivastava, R A Padua, C Chomienne, B George, P Balasubramanian, V Mathews
Arsenic trioxide (ATO) mediates PML-RARA oncoprotein degradation via the proteasome pathway and this degradation appears to be critical for achieving cure in acute promyeloytic leukemia (APL). We have previously demonstrated significant micro-environment mediated drug resistance (EMDR) to arsenic trioxide (ATO) in APL. Here we demonstrate that this EMDR could be effectively overcome by combining a proteasome inhibitor (bortezomib) with ATO. A synergistic effect on combining these two agents, in-vitro, was noted in both ATO sensitive and ATO resistant APL cell lines...
August 18, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Sonia Missiroli, Massimo Bonora, Simone Patergnani, Federica Poletti, Mariasole Perrone, Roberta Gafà, Eros Magri, Andrea Raimondi, Giovanni Lanza, Carlo Tacchetti, Guido Kroemer, Pier Paolo Pandolfi, Paolo Pinton, Carlotta Giorgi
The precise molecular mechanisms that coordinate apoptosis and autophagy in cancer remain to be determined. Here, we provide evidence that the tumor suppressor promyelocytic leukemia protein (PML) controls autophagosome formation at mitochondria-associated membranes (MAMs) and, thus, autophagy induction. Our in vitro and in vivo results demonstrate how PML functions as a repressor of autophagy. PML loss promotes tumor development, providing a growth advantage to tumor cells that use autophagy as a cell survival strategy during stress conditions...
August 30, 2016: Cell Reports
Chang-Fang Chiu, Jing-Ru Weng, Appaso Jadhav, Chia-Yung Wu, Aaron M Sargeant, Li-Yuan Bai
T315, an integrin-linked kinase (ILK) inhibitor, has been shown to suppress the proliferation of breast cancer, stomach cancer and chronic lymphocytic leukemia cells. Here we demonstrate that T315 decreases cell viability of acute myeloid leukemia (AML) cell lines (HL-60 and THP-1) and primary leukemia cells from AML patients in a dose-responsive manner. Normal human bone marrow cells are less sensitive than leukemia cells to T315. T315 down regulates protein kinase B (Akt) and p-Akt and induces caspase activation, poly-ADP-ribose polymerase (PARP) cleavage, apoptosis and autophagy through an ILK-independent manner...
2016: International Journal of Molecular Sciences
Yu-Jen Chen, Li-Wen Fang, Wen-Chi Su, Wen-Yi Hsu, Kai-Chien Yang, Huey-Lan Huang
Lapatinib is an oral-form dual tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR or ErbB/Her) superfamily members with anticancer activity. In this study, we examined the effects and mechanism of action of lapatinib on several human leukemia cells lines, including acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and acute lymphoblastic leukemia (ALL) cells. We found that lapatinib inhibited the growth of human AML U937, HL-60, NB4, CML KU812, MEG-01, and ALL Jurkat T cells. Among these leukemia cell lines, lapatinib induced apoptosis in HL-60, NB4, and Jurkat cells, but induced nonapoptotic cell death in U937, K562, and MEG-01 cells...
2016: OncoTargets and Therapy
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