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      Inhibition of CaMKIIα Activity Enhances Antitumor Effect of Fullerene C60 Nanocrystals by Suppression of Autophagic Degradation

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          Abstract

          Fullerene C60 nanocrystals (nano‐C60) possess various attractive bioactivities, including autophagy induction and calcium/calmodulin‐dependent protein kinase IIα (CaMKIIα) activation. CaMKIIα is a multifunctional protein kinase involved in many cellular processes including tumor progression; however, the biological effects of CaMKIIα activity modulated by nano‐C60 in tumors have not been reported, and the relationship between CaMKIIα activity and autophagic degradation remains unclear. Herein, nano‐C60 is demonstrated to elicit reactive oxygen species (ROS)‐dependent cytotoxicity and persistent activation of CaMKIIα in osteosarcoma (OS) cells. CaMKIIα activation, in turn, produces a protective effect against cytotoxicity from nano‐C60 itself. Inhibition of CaMKIIα activity by either the chemical inhibitor KN‐93 or CaMKIIα knockdown dramatically promotes the anti‐OS effect of nano‐C60. Moreover, inhibition of CaMKIIα activity causes lysosomal alkalinization and enlargement, and impairs the degradation function of lysosomes, leading to autophagosome accumulation. Importantly, excessive autophagosome accumulation and autophagic degradation blocking are shown to play an important role in KN‐93‐enhanced‐OS cell death. The synergistic anti‐OS efficacy of KN‐93 and nano‐C60 is further revealed in an OS‐xenografted murine model. The results demonstrate that CaMKIIα inhibition, along with the suppression of autophagic degradation, presents a promising strategy for improving the antitumor efficacy of nano‐C60.

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          Gold nanoparticles induce autophagosome accumulation through size-dependent nanoparticle uptake and lysosome impairment.

          Development of nanotechnology calls for a comprehensive understanding of the impact of nanomaterials on biological systems. Autophagy is a lysosome-based degradative pathway which plays an essential role in maintaining cellular homeostasis. Previous studies have shown that nanoparticles from various sources can induce autophagosome accumulation in treated cells. However, the underlying mechanism is still not clear. Gold nanoparticles (AuNPs) are one of the most widely used nanomaterials and have been reported to induce autophagosome accumulation. In this study, we found that AuNPs can be taken into cells through endocytosis in a size-dependent manner. The internalized AuNPs eventually accumulate in lysosomes and cause impairment of lysosome degradation capacity through alkalinization of lysosomal pH. Consistent with previous studies, we found that AuNP treatment can induce autophagosome accumulation and processing of LC3, an autophagosome marker protein. However, degradation of the autophagy substrate p62 is blocked in AuNP-treated cells, which indicates that autophagosome accumulation results from blockade of autophagy flux, rather than induction of autophagy. Our data clarify the mechanism by which AuNPs induce autophagosome accumulation and reveal the effect of AuNPs on lysosomes. This work is significant to nanoparticle research because it illustrates how nanoparticles can potentially interrupt the autophagic pathway and has important implications for biomedical applications of nanoparticles. © 2011 American Chemical Society
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            Calcium-activated chloride channel ANO1 promotes breast cancer progression by activating EGFR and CAMK signaling.

            The calcium-activated chloride channel anoctamin 1 (ANO1) is located within the 11q13 amplicon, one of the most frequently amplified chromosomal regions in human cancer, but its functional role in tumorigenesis has remained unclear. The 11q13 region is amplified in ∼15% of breast cancers. Whether ANO1 is amplified in breast tumors, the extent to which gene amplification contributes to ANO1 overexpression, and whether overexpression of ANO1 is important for tumor maintenance have remained unknown. We have found that ANO1 is amplified and highly expressed in breast cancer cell lines and primary tumors. Amplification of ANO1 correlated with disease grade and poor prognosis. Knockdown of ANO1 in ANO1-amplified breast cancer cell lines and other cancers bearing 11q13 amplification inhibited proliferation, induced apoptosis, and reduced tumor growth in established cancer xenografts. Moreover, ANO1 chloride channel activity was important for cell viability. Mechanistically, ANO1 knockdown or pharmacological inhibition of its chloride-channel activity reduced EGF receptor (EGFR) and calmodulin-dependent protein kinase II (CAMKII) signaling, which subsequently attenuated AKT, v-src sarcoma viral oncogene homolog (SRC), and extracellular signal-regulated kinase (ERK) activation in vitro and in vivo. Our results highlight the involvement of the ANO1 chloride channel in tumor progression and provide insights into oncogenic signaling in human cancers with 11q13 amplification, thereby establishing ANO1 as a promising target for therapy in these highly prevalent tumor types.
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              Photothermally enhanced drug delivery by ultrasmall multifunctional FeCo/graphitic shell nanocrystals.

              FeCo/graphitic carbon shell (FeCo/GC) nanocrystals (∼4-5 nm in diameter) with ultrahigh magnetization are synthesized, functionalized, and developed into multifunctional biocompatible materials. We demonstrate the ability of this material to serve as an integrated system for combined drug delivery, near-infrared (NIR) photothermal therapy, and magnetic resonance imaging (MRI) in vitro. We show highly efficient loading of doxorubicin (DOX) by π-stacking on the graphitic shell to afford FeCo/GC-DOX complexes and pH sensitive DOX release from the particles. We observe enhanced intracellular drug delivery by FeCo/GC-DOX under 20 min of NIR laser (808 nm) induced hyperthermia to 43 °C, resulting in a significant increase of FeCo/GC-DOX toxicity toward breast cancer cells. The synergistic cancer cell killing by FeCo/GC-DOX drug delivery under photothermal heating is due to a ∼two-fold enhancement of cancer cell uptake of FeCo/GC-DOX complex and the increased DOX toxicity under the 43 °C hyperthermic condition. The combination of synergistic NIR photothermally enhanced drug delivery and MRI with the FeCo/GC nanocrystals could lead to a powerful multimodal system for biomedical detection and therapy.
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                Author and article information

                Contributors
                jxding@ciac.ac.cn
                hua_yingqi@163.com
                caizhengdong@sjtu.edu.cn
                Journal
                Adv Sci (Weinh)
                Adv Sci (Weinh)
                10.1002/(ISSN)2198-3844
                ADVS
                Advanced Science
                John Wiley and Sons Inc. (Hoboken )
                2198-3844
                10 February 2019
                17 April 2019
                : 6
                : 8 ( doiID: 10.1002/advs.v6.8 )
                : 1801233
                Affiliations
                [ 1 ] Department of Orthopedics Shanghai General Hospital Shanghai Jiao Tong University School of Medicine Shanghai Bone Tumor Institution 100 Haining Street Shanghai 200080 P. R. China
                [ 2 ] Shanghai Bone Tumor Institution 100 Haining Street Shanghai 200080 P. R. China
                [ 3 ] Hefei National Laboratory for Physical Sciences at the Microscale and School of Life Sciences University of Science and Technology of China 96 Jinzhai Street Hefei 230026 P. R. China
                [ 4 ] Division of Engineering in Medicine Department of Medicine Brigham and Women's Hospital Harvard Medical School 65 Landsdowne Street Cambridge MA 02139 USA
                [ 5 ] School of Medicine South China University of Technology Nanobio Laboratory Institutes for Life Sciences South China University of Technology 381 Wushan Street Guangzhou 510006 P. R. China
                [ 6 ] Key Laboratory of Gene Engineering of the Ministry of Education State Key Laboratory of Biocontrol School of Life Sciences Sun Yat‐sen University 135 West Xingang Street Guangzhou 510275 P. R. China
                [ 7 ] Key Laboratory of Polymer Ecomaterials Changchun Institute of Applied Chemistry Chinese Academy of Sciences 5625 Renmin Street Changchun 130022 P. R. China
                Author notes
                Author information
                https://orcid.org/0000-0002-5232-8863
                Article
                ADVS1018
                10.1002/advs.201801233
                6468974
                31016106
                4a5f5dde-9226-49df-b036-be3f224d31c7
                © 2019 The Authors. Published by WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 30 July 2018
                : 04 December 2018
                Page count
                Figures: 9, Tables: 0, Pages: 15, Words: 7274
                Funding
                Funded by: National Natural Science Foundation of China
                Award ID: 81501584
                Award ID: 81672651
                Award ID: 81502604
                Award ID: 81702973
                Award ID: 51873207
                Award ID: 51673190
                Award ID: 51603204
                Award ID: 51673187
                Funded by: Excellent Young Fund of Shanghai General Hospital
                Award ID: 06N1702006
                Funded by: Shanghai Municipal Health and Family Planning Commission
                Award ID: 20164Y0270
                Funded by: Shanghai Hospital Development Center
                Award ID: 16CR3010A
                Categories
                Full Paper
                Full Papers
                Custom metadata
                2.0
                advs1018
                April 17, 2019
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.6.2.1 mode:remove_FC converted:17.04.2019

                autophagic degradation,autophagy,calcium/calmodulin‐dependent protein kinase iiα,fullerene c60 nanocrystals,osteosarcoma therapy

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