Novel monofunctional platinum (II) complex Mono-Pt induces apoptosis-independent autophagic cell death in human ovarian carcinoma cells,distinct from cisplatin |
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Authors: | Wen-Jie Guo Yang-Miao Zhang Li Zhang Bin Huang Fei-Fei Tao Wei Chen Zi-Jian Guo Qiang Xu Yang Sun |
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Institution: | 1.State Key Laboratory of Pharmaceutical Biotechnology; School of Life Sciences; Nanjing University; Nanjing, China;2.State Key Laboratory of Coordination Chemistry; Coordination Chemistry Institute; Nanjing University; Nanjing, China;3.Key Laboratory of Nuclear Medicine; Ministry of Health; Jiangsu Key Laboratory of Molecular Nuclear Medicine; Jiangsu Institute of Nuclear Medicine; Wuxi, China |
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Abstract: | Failure to engage apoptosis appears to be a leading mechanism of resistance to traditional platinum drugs in patients with ovarian cancer. Therefore, an alternative strategy to induce cell death is needed for the chemotherapy of this apoptosis-resistant cancer. Here we report that autophagic cell death, distinct from cisplatin-induced apoptosis, is triggered by a novel monofunctional platinum (II) complex named Mono-Pt in human ovarian carcinoma cells. Mono-Pt-induced cell death has the following features: cytoplasmic vacuolation, caspase-independent, no nuclear fragmentation or chromatin condensation, and no apoptotic bodies. These characteristics integrally indicated that Mono-Pt, rather than cisplatin, initiated a nonapoptotic cell death in Caov-3 ovarian carcinoma cells. Furthermore, incubation of the cells with Mono-Pt but not with cisplatin produced an increasing punctate distribution of microtubule-associated protein 1 light chain 3 (LC3), and an increasing ratio of LC3-II to LC3-I. Mono-Pt also caused the formation of autophagic vacuoles as revealed by monodansylcadaverine staining and transmission electron microscopy. In addition, Mono-Pt-induced cell death was significantly inhibited by the knockdown of either BECN1 or ATG7 gene expression, or by autophagy inhibitors 3-methyladenine, chloroquine and bafilomycin A1. Moreover, the effect of Mono-Pt involved the AKT1-MTOR-RPS6KB1 pathway and MAPK1 (ERK2)/MAPK3 (ERK1) signaling, since the MTOR inhibitor rapamycin increased, while the MAPK1/3 inhibitor U0126 decreased Mono-Pt-induced autophagic cell death. Taken together, our results suggest that Mono-Pt exerts anticancer effect via autophagic cell death in apoptosis-resistant ovarian cancer. These findings lead to increased options for anticancer platinum drugs to induce cell death in cancer. |
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Keywords: | autophagy monofunctional platinum complex cisplatin AKT1 MAPK1/3 |
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