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    • In the present study we firstly

    2019-05-16

    In the present study, we firstly confirmed the resistance of osteosarcoma U2OS ekb-569 to doxorubicin under hypoxia via inhibiting the drug-induced apoptosis. The hypoxia pre-treatment could significantly ameliorate the viability reduction in U2-os cells which were treated with doxorubicin with 5, 10, 20 or 40μM. And less apoptotic U2-os cells were induced, and less cleaved caspase (activated form) and less lyzed PARP were promoted by the doxorubicin treatment in the hypoxia group. Therefore, hypoxia reduces the sensitivity of osteosarcoma cells to doxorubicin in either MG-63 or U2-os osteosarcoma cells. Then we investigated the role of HIF-1α, which is the best characterized marker for hypoxia [32,31], in the hypoxia-mediated resistance of U2-os cells to doxorubicin. Interestingly, HIF-1α was significantly promoted by hypoxia in U2-os cells which were treated with doxorubicin, whereas exerted no influence on the sensitivity of U2-os cells to doxorubicin. Reactive oxygen species (ROS) has been conceived to be promoted under hypoxia and to trigger the AMPK activation, independent of an increase in AMP/ATP ratio [34,33]. In the present study, we also confirmed the activation of AMPK by hypoxia in U2-os cells. Markedly increased ROS was indicated in the U2-os cells under hypoxia. And significantly upregulated levels of phosphorylated AMPK and phosphorylated ACC, both of which are the active forms of AMPK signaling, were also promoted in the U2-os cells under hypoxia. And the levels of phosphorylated AMPK and phosphorylated ACC were significantly up-regulated by the AMPK activator, AICAR, or downregulated by AMPK inhibitor, Compound C in the doxorubicin-treated U2-os cells. Moreover, AMPK signaling has been recognized to involve in the hypoxia-mediated drug resistance in several types of cancers, such as non–small cell lung cancers to cisplatin and doxorubicin [41], prostate cancers [42]. However, there was a controversy about the activation of AMPK signaling in the drug resistance. AMPK is activated in the prostate cancer cells [42], while is inactivated in the lung cancer cells [41], during hypoxia leading to drug resistance, implying a cancer type-dependence. And the present study also confirmed the activation of AMPK signaling during the hypoxia-induced drug resistance in osteosarcoma cells. The chemical manipulation of AMPK signaling regulates the sensitivity of osteosarcoma cells to doxorubicin. The promotion by AICAR and the reduction by Compound C to the AMPK signaling significantly ameliorated or deteriorated the viability reduction or apoptosis induction of U2-os cells under hypoxia. In addition, the level of cleaved caspase 3 and the lyzed PARP were also reduced by the treatment with AICAR, whereas were upregulated by Compound C. Thus, the AMPK signaling mediated the hypoxia-induced resistance of U2-os cells to doxorubicin. Autophagy is a dynamic self-degradation process for cellular components by cellular lysosome under a stringent regulation [43,44], and has also been recognized during ischemic heart disease [45]. Autophagy normally maintains at a low level in heart, and is sharply promoted as a response to such environmental stress conditions as ATP depletion, excessive ROS and mitochondrial dysfunction [46,47]. Moreover, autophagy has been identified to mediate the hypoxia-induced resistance by regulating the angiogenesis in malignancies [48]. The present study has recognized the involvement of autophagy in the hypoxia-induced resistance in osteosarcoma cells. However, it is not clear about the orchestrated pathways about AMPK signaling and autophagy promotion during the hypoxia-induced resistance. The reduced adenosine-triphosphate (ATP) has been recognized to activate autophay [49]. The increased AMP/ATP ratio activates AMP-activated protein kinase (AMPK) [50], which successively induces autophagy via inhibiting mammalian target of rapamycin (mTOR) [46]. The promoted reactive oxygen species (ROS) has also been recognized to induce autophagy in cardiocytes [51], in choriocarcinoma cells [52], and in breast cancer cells [53]. Therefore, the role of autophagy in the AMPK-mediated chemoresistance of osteocarcoma cells needs to be further clarified.