title: Graphene oxide as a chemosensitizer: diverted autophagic flux, enhanced nuclear import, elevated necrosis and improved antitumor effects.
abstract: Graphene oxide (GO) is a nanomaterial that provokes autophagy in CT26 colon cancer cells and confers antitumor effects. Here we demonstrated that both GO and the chemotherapy drug cisplatin (CDDP) induced autophagy but elicited low degrees of CT26 cell death. Strikingly, GO combined with CDDP (GO/CDDP) potentiated the CT26 cell killing via necrosis. GO/CDDP not only elicited autophagy, but induced the nuclear import of CDDP and the autophagy marker LC3. The nuclear LC3 did not co-localize with p62 or Lamp-2, neither did blocking autolysosome formation significantly hinder the nuclear import of LC3/CDDP and necrosis, indicating that autophagosome and autolysosome formation was dispensable. Conversely, suppressing phagophore formation and importin-α/β significantly alleviated the nuclear import of LC3/CDDP and necrosis. These data suggested that GO/CDDP diverted the LC3 flux in the early phase of autophagy, resulting in LC3 trafficking towards the nucleus in an importin-α/β-dependent manner, which concurred with the CDDP nuclear import and necrosis. Intratumoral injection of GO/CDDP into mice bearing CT26 colon tumors potentiated immune cell infiltration and promoted cell death, autophagy and HMGB1 release, thereby synergistically augmenting the antitumor effects. Altogether, we unveiled a mechanism concerning how nanomaterials chemosensitize cancer cells and demonstrated the potentials of GO as a chemosensitizer.
authors.affiliation: Department of Chemical Engineering, National Tsing Hua University, Hsinchu 300, Taiwan.
authors.forename: Guan-Yu
authors.initials: GY
authors.lastname: Chen
authors.affiliation: Department of Chemical Engineering, National Tsing Hua University, Hsinchu 300, Taiwan.
authors.forename: Chia-Le
authors.initials: CL
authors.lastname: Meng
authors.affiliation: Department of Chemical Engineering, National Tsing Hua University, Hsinchu 300, Taiwan; Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu 300, Taiwan.
authors.forename: Kuan-Chen
authors.initials: KC
authors.lastname: Lin
authors.affiliation: Department of Chemical Engineering, National Tsing Hua University, Hsinchu 300, Taiwan.
authors.forename: Hsing-Yu
authors.initials: HY
authors.lastname: Tuan
authors.affiliation: Department of Chemical Engineering, National Tsing Hua University, Hsinchu 300, Taiwan.
authors.forename: Hong-Jie
authors.initials: HJ
authors.lastname: Yang
authors.affiliation: Department of Chemical Engineering, National Tsing Hua University, Hsinchu 300, Taiwan.
authors.forename: Chiu-Ling
authors.initials: CL
authors.lastname: Chen
authors.affiliation: Department of Chemical Engineering, National Tsing Hua University, Hsinchu 300, Taiwan.
authors.forename: Kuei-Chang
authors.initials: KC
authors.lastname: Li
authors.affiliation: Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu 300, Taiwan.
authors.forename: Chi-Shiun
authors.initials: CS
authors.lastname: Chiang
authors.affiliation: Department of Chemical Engineering, National Tsing Hua University, Hsinchu 300, Taiwan. Electronic address: ychu@mx.nthu.edu.tw.
authors.forename: Yu-Chen
authors.initials: YC
authors.lastname: Hu
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001343:Autophagy / Q000187:drug effects; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology / Q000627:therapeutic use; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D006108:Graphite / Q000494:pharmacology / Q000627:therapeutic use*; D008807:Mice, Inbred BALB C; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009336:Necrosis; D010087:Oxides / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D010087:Oxides; D006108:Graphite; D002945:Cisplatin
keywords: Autophagy; Chemoresistance; Cisplatin; Graphene oxide; Necrosis; Nuclear import