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      Reversine Induced Multinucleated Cells, Cell Apoptosis and Autophagy in Human Non-Small Cell Lung Cancer Cells

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          Abstract

          Reversine, an A3 adenosine receptor antagonist, has been shown to induce differentiated myogenic-lineage committed cells to become multipotent mesenchymal progenitor cells. We and others have reported that reversine has an effect on human tumor suppression. This study revealed anti-tumor effects of reversine on proliferation, apoptosis and autophagy induction in human non-small cell lung cancer cells. Treatment of these cells with reversine suppressed cell growth in a time- and dosage-dependent manner. Moreover, polyploidy occurred after reversine treatment. In addition, caspase-dependent apoptosis and activation of autophagy by reversine in a dosage-dependent manner were also observed. We demonstrated in this study that reversine contributes to growth inhibition, apoptosis and autophagy induction in human lung cancer cells. Therefore, reversine used as a potential therapeutic agent for human lung cancer is worthy of further investigation.

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          Cell death by mitotic catastrophe: a molecular definition.

          Maria Castedo, Jean-Luc Perfettini, Thomas Roumier … (2004)
          The current literature is devoid of a clearcut definition of mitotic catastrophe, a type of cell death that occurs during mitosis. Here, we propose that mitotic catastrophe results from a combination of deficient cell-cycle checkpoints (in particular the DNA structure checkpoints and the spindle assembly checkpoint) and cellular damage. Failure to arrest the cell cycle before or at mitosis triggers an attempt of aberrant chromosome segregation, which culminates in the activation of the apoptotic default pathway and cellular demise. Cell death occurring during the metaphase/anaphase transition is characterized by the activation of caspase-2 (which can be activated in response to DNA damage) and/or mitochondrial membrane permeabilization with the release of cell death effectors such as apoptosis-inducing factor and the caspase-9 and-3 activator cytochrome c. Although the morphological aspect of apoptosis may be incomplete, these alterations constitute the biochemical hallmarks of apoptosis. Cells that fail to execute an apoptotic program in response to mitotic failure are likely to divide asymmetrically in the next round of cell division, with the consequent generation of aneuploid cells. This implies that disabling of the apoptotic program may actually favor chromosomal instability, through the suppression of mitotic catastrophe. Mitotic catastrophe thus may be conceived as a molecular device that prevents aneuploidization, which may participate in oncogenesis. Mitotic catastrophe is controlled by numerous molecular players, in particular, cell-cycle-specific kinases (such as the cyclin B1-dependent kinase Cdk1, polo-like kinases and Aurora kinases), cell-cycle checkpoint proteins, survivin, p53, caspases and members of the Bcl-2 family.
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            Tumor cell-specific bioluminescence platform to identify stroma-induced changes to anti-cancer drug activity

            Douglas W. McMillin, Jake Delmore, Ellen Weisberg … (2010)
            Conventional anti-cancer drug screening is typically performed in the absence of accessory cells of the tumor microenvironment, which can profoundly alter anti-tumor drug activity. To address this major limitation, we developed the tumor cell-specific in vitro bioluminescence imaging (CS-BLI) assay. Tumor cells (e.g. myeloma, leukemia and solid tumors) stably expressing luciferase are co-cultured with non-malignant accessory cells (e.g. stromal cells) for selective quantification of tumor cell viability, in presence vs. absence of stromal cells or drug treatment. CS-BLI is high-throughput scalable and identifies stroma-induced chemoresistance in diverse malignancies, including imatinib-resistance in leukemic cells. A stromal-induced signature in tumor cells correlates with adverse clinical prognosis and includes signatures for activated Akt, Ras, NF-κB, HIF-1α, myc, hTERT, and IRF4; signatures for biological aggressiveness and for self-renewal. Unlike conventional screening, CS-BLI can also identify agents with increased activity against tumor cells interacting with stroma. One such compound, reversine, exhibits more potent activity in an orthotopic model of diffuse myeloma bone lesions than in conventional subcutaneous xenografts. Use of CS-BLI, therefore, enables refined screening of candidate anti-cancer agents to enrich preclinical pipelines with potential therapeutics that overcome stroma-mediated drug resistance and can act in a synthetic lethal manner in the context of tumor-stromal interactions.
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              Aurora kinase A inhibition-induced autophagy triggers drug resistance in breast cancer cells.

              Zhengzhi Zou, Zhongyu Yuan, Qiongxia Zhang … (2012)
              We have previously shown that elevated expression of mitotic kinase aurora kinase A (AURKA) in cancer cells promotes the development of metastatic phenotypes and is associated clinically with adverse prognosis. Here, we first revealed a clinically positive correlation between AURKA and autophagy-associated protein SQSTM1 in breast cancer and further demonstrated that AURKA regulated SQSTM1 through autophagy. Indeed, depletion by siRNA or chemical inhibition of AURKA by the small molecule VX-680 increased both the level of microtubule-associated protein 1 light chain 3-II (LC3-II) and the number of autophagosomes, along with decreased SQSTM1. Conversely, overexpression of AURKA inhibited autophagy, as assessed by decreased LC3-II and increased SQSTM1 either upon nutrient deprivation or normal conditions. In addition, phosphorylated forms of both RPS6KB1 and mechanistic target of rapamycin (MTOR) were elevated by overexpression of AURKA whereas they were suppressed by depletion or inhibition of AURKA. Moreover, inhibition of MTOR by PP242, an inhibitor of MTOR complex1/2, abrogated the changes in both LC3-II and SQSTM1 in AURKA-overexpressing BT-549 cells, suggesting that AURKA-suppressed autophagy might be associated with MTOR activation. Lastly, repression of autophagy by depletion of either LC3 or ATG5, sensitized breast cancer cells to VX-680-induced apoptosis. Similar findings were observed in cells treated with the autophagy inhibitors chloroquine (CQ) and bafilomycin A 1 (BAF). Our data thus revealed a novel role of AURKA as a negative regulator of autophagy, showing that AURKA inhibition induced autophagy, which may represent a novel mechanism of drug resistance in apoptosis-aimed therapy for breast cancer.
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                Author and article information

                Contributors
                Swati Palit Deb: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, CA USA )
                ISSN (Electronic): 1932-6203
                Publication date (Electronic): 6 July 2016
                Publication date Collection: 2016
                Volume: 11
                Issue: 7
                Electronic Location Identifier: e0158587
                Affiliations
                [1 ]Department of Health and Nutrition, Chia Nan University of Pharmacy and Science, Tainan, Taiwan
                [2 ]Division of Hematology-Oncology, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan
                [3 ]Department of Medical Research, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan
                [4 ]Department of Medical Laboratory Science and Biotechnology, College of Medicine and Life Science, Chung Hwa University of Medical Technology, Tainan, Taiwan
                [5 ]Department of Biochemical Science and Technology, National Chiayi University, Chiayi, Taiwan
                [6 ]Department of Internal Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan
                Virginia Commonwealth University, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: YCL YRL YST. Performed the experiments: YRL JDL YYC PTC. Analyzed the data: YCL YRL JDL YYC PTC YST. Contributed reagents/materials/analysis tools: YCL YRL YST. Wrote the paper: YCL YRL YYC YST.

                Article
                Publisher ID: PONE-D-15-47215
                DOI: 10.1371/journal.pone.0158587
                PMC ID: 4934785
                PubMed ID: 27385117
                SO-VID: 983329dc-503a-4fbf-99f9-d336b6d3371a
                Copyright © © 2016 Lu et al
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 28 October 2015
                Date accepted : 17 June 2016
                Page count
                Figures: 6, Tables: 0, Pages: 14
                Funding
                Funded by: Ditmanson Medical Foundation Chia-Yi Christian Hospital
                Award ID: Grant R99-20
                Award Recipient :
                Funded by: Chung Hwa University of Medical Technology
                Award ID: Grant 1011001
                Award Recipient :
                This study was supported by research grants from Chiayi Christian Hospital (Grant R99-20), the Ministry of Science and Technology, ROC (MOST 104-2314-B-705-003), and Chung Hwa University of Medical Technology (Grant 1011001). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Subject: Research Article
                Subject: Medicine and Health Sciences
                Subject: Oncology
                Subject: Cancers and Neoplasms
                Subject: Lung and Intrathoracic Tumors
                Subject: Non-Small Cell Lung Cancer
                Subject: Biology and Life Sciences
                Subject: Cell Biology
                Subject: Cell Processes
                Subject: Cell Death
                Subject: Apoptosis
                Subject: Biology and Life Sciences
                Subject: Cell Biology
                Subject: Cell Processes
                Subject: Cell Death
                Subject: Autophagic Cell Death
                Subject: Medicine and Health Sciences
                Subject: Oncology
                Subject: Cancer Treatment
                Subject: Medicine and Health Sciences
                Subject: Oncology
                Subject: Cancers and Neoplasms
                Subject: Lung and Intrathoracic Tumors
                Subject: Small Cell Lung Cancer
                Subject: Research and Analysis Methods
                Subject: Specimen Preparation and Treatment
                Subject: Staining
                Subject: Cell Staining
                Subject: Biology and Life Sciences
                Subject: Cell Biology
                Subject: Cell Processes
                Subject: Cell Growth
                Subject: Biology and Life Sciences
                Subject: Cell Biology
                Subject: Cell Processes
                Subject: Cell Cycle and Cell Division
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                Data Availability All relevant data are within the paper.

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