5
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      CNOT2 Is Critically Involved in Atorvastatin Induced Apoptotic and Autophagic Cell Death in Non-Small Cell Lung Cancers

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Though Atorvastatin has been used as a hypolipidemic agent, its anticancer mechanisms for repurposing are not fully understood so far. Thus, in the current study, its apoptotic and autophagic mechanisms were investigated in non-small cell lung cancers (NSCLCs). Atorvastatin increased cytotoxicity, sub G1 population, the number of apoptotic bodies, cleaved poly (ADP-ribose) polymerase (PARP) and caspase 3 and activated p53 in H1299, H596, and H460 cells. Notably, Atorvastatin inhibited the expression of c-Myc and induced ribosomal protein L5 and L11, but depletion of L5 reduced PARP cleavages induced by Atorvastatin rather than L11 in H1299 cells. Also, Atorvastatin increased autophagy microtubule-associated protein 1A/1B-light chain 3II (LC3 II) conversion, p62/sequestosome 1 (SQSTM1) accumulation with increased number of LC3II puncta in H1299 cells. However, late stage autophagy inhibitor chloroquine (CQ) increased cytotoxicity in Atorvastatin treated H1299 cells compared to early stage autophagy inhibitor 3-methyladenine (3-MA). Furthermore, autophagic flux assay using RFP-GFP-LC3 constructs and Lysotracker Red or acridine orange-staining demonstrated that autophagosome-lysosome fusion is blocked by Atorvastatin treatment in H1299 cells. Conversely, overexpression of CCR4-NOT transcription complex subunit 2(CNOT2) weakly reversed the ability of Atorvastatin to increase cytotoxicity, sub G1 population, cleavages of PARP and caspase 3, LC3II conversion and p62/SQSTM1 accumulation in H1299 cells. In contrast, CNOT2 depletion enhanced cleavages of PARP and caspase 3, LC3 conversion and p62/SQSTM1 accumulation in Atorvastatin treated H1299 cells. Overall, these findings suggest that CNOT2 signaling is critically involved in Atorvastatin induced apoptotic and autophagic cell death in NSCLCs.

          Related collections

          Most cited references30

          • Record: found
          • Abstract: found
          • Article: not found

          Autophagy-dependent cell death

          Autophagy-dependent cell death can be defined as cell demise that has a strict requirement of autophagy. Although autophagy often accompanies cell death following many toxic insults, the requirement of autophagic machinery for cell death execution, as established through specific genetic or chemical inhibition of the process, is highly contextual. During animal development, perhaps the best validated model of autophagy-dependent cell death is the degradation of the larval midgut during larval-pupal metamorphosis, where a number of key autophagy genes are required for the removal of the tissues. Surprisingly though, even in the midgut, not all of the 'canonical' autophagic machinery appears to be required. In other organisms and cancer cells many variations of autophagy-dependent cell death are apparent, pointing to the lack of a unifying cell death pathway. It is thus possible that components of the autophagy machinery are selectively utilised or repurposed for this type of cell death. In this review, we discuss examples of cell death that utilise autophagy machinery (or part thereof), the current knowledge of the complexity of autophagy-dependent cellular demise and the potential mechanisms and regulatory pathways involved in such cell death.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Signaling to p53: ribosomal proteins find their way.

            Inherently disparate cell growth and division, which are intimately coupled through a delicate network of intracellular and extracellular signaling, require ribosomal biogenesis. A number of events imparting instability to ribosomal biogenesis can cause nucleolar stress. In response to this stress, several ribosomal proteins bind to MDM2 and block MDM2-mediated p53 ubiquitination and degradation, resulting in p53-dependent cell cycle arrest. By doing so, the ribosomal proteins play a crucial role in connecting deregulated cell growth with inhibition of cell division. The ribosomal protein-MDM2-p53 signaling pathway provides a molecular switch that may constitute a surveillance network monitoring the integrity of ribosomal biogenesis.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: found
              Is Open Access

              Autophagy: An Essential Degradation Program for Cellular Homeostasis and Life

              Autophagy is a lysosome-dependent cellular degradation program that responds to a variety of environmental and cellular stresses. It is an evolutionarily well-conserved and essential pathway to maintain cellular homeostasis, therefore, dysfunction of autophagy is closely associated with a wide spectrum of human pathophysiological conditions including cancers and neurodegenerative diseases. The discovery and characterization of the kingdom of autophagy proteins have uncovered the molecular basis of the autophagy process. In addition, recent advances on the various post-translational modifications of autophagy proteins have shed light on the multiple layers of autophagy regulatory mechanisms, and provide novel therapeutic targets for the treatment of the diseases.
                Bookmark

                Author and article information

                Journal
                Cancers (Basel)
                Cancers (Basel)
                cancers
                Cancers
                MDPI
                2072-6694
                30 September 2019
                October 2019
                : 11
                : 10
                : 1470
                Affiliations
                College of Korean Medicine, Kyung Hee University, Seoul 02447, Korea; jhlee096@ 123456naver.com (J.L.); johnsperfume@ 123456gmail.com (J.H.J.); hjsung0103@ 123456naver.com (J.H.); wdnk77@ 123456naver.com (J.E.P.); 964juha@ 123456daum.net (J.-H.K.); wy1319@ 123456naver.com (W.Y.P.); jysuh3670@ 123456gmail.com (J.Y.S.)
                Author notes
                [* ]Correspondence: sungkim7@ 123456khu.ac.kr ; Tel.: +82-2-961-9233
                [†]

                These authors contributed equally to this work.

                Author information
                https://orcid.org/0000-0002-5644-5960
                https://orcid.org/0000-0003-2423-1973
                Article
                cancers-11-01470
                10.3390/cancers11101470
                6826547
                31574980
                6747cfef-8b97-45c2-a874-c1b3a07ec8df
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 14 August 2019
                : 26 September 2019
                Categories
                Article

                atorvastatin,non-small lung cancer cells,apoptosis,autophagy,cnot2

                Comments

                Comment on this article