PMID- 26998423 OWN - NLM STAT- PubMed-not-MEDLINE DCOM- 20160321 LR - 20201001 IS - 2212-1366 (Print) IS - 2212-1374 (Electronic) IS - 2212-1366 (Linking) VI - 5 IP - 1 DP - 2016 Mar TI - Hypoxia promotes drug resistance in osteosarcoma cells via activating AMP-activated protein kinase (AMPK) signaling. PG - 22-9 LID - 10.1016/j.jbo.2016.01.002 [doi] AB - PURPOSE: Drug resistance has been recognized to be a major obstacle to the chemotherapy for osteosarcoma. And the potential importance of hypoxia as a target to reverse drug resistance in osteosarcoma has been indicated, though the mechanism underlining such role is not clarified. The present study aims to investigate the role of hypoxia in the drug resistance in osteosarcoma cells via activating AMP-activated protein kinase (AMPK) signaling. EXPERIMENTAL DESIGN: We investigated the promotion of the resistance to doxorubicin of osteosarcoma MG-63 and U2-os cells in vitro, and then determined the role of hypoxia-inducible factor-1 (HIF-1)alpha and HIF-1beta, the activation and regulatory role of AMPK in the osteosarcoma U2-os cells which were treated with doxorubicin under hypoxia. RESULTS: It was demonstrated that hypoxia significantly reduced the sensitivity of MG-63 and U2-os cells to doxorubicin, indicating an inhibited viability reduction and a reduced apoptosis promotion. And such reduced sensitivity was not associated with HIF-1alpha, though it was promoted by hypoxia in U2-os cells. Interestingly, the AMPK signaling was significantly promoted by hypoxia in the doxorubicin-treated U2-os cells, with a marked upregulation of phosphorylated AMPK (Thr 172) and phosphorylated acetyl-CoA carboxylase (ACC) (Ser 79), which were sensitive to the AMPK activator, AICAR and the AMPK inhibitor, Compound C. Moreover, the promoted AMPK activity by AICAR or the downregulated AMPK activity by Compound C significantly reduced or promoted the sensitivity of U2-os cells to doxorubicin. CONCLUSION: The present study confirmed the AMPK signaling activation in the doxorubicin-treated osteosarcoma cells, in response to hypoxia, and the chemical upregulation or downregulation of AMPK signaling reduced or increased the chemo-sensitivity of osteosarcoma U2-os cells in vitro. Our study implies that AMPK inhibition might be a effective strategy to sensitize osteocarcoma cells to chemotherapy. FAU - Zhao, Changfu AU - Zhao C AD - Department of Orthopedics, China-Japan Union Hospital of Jilin University, No. 126 of Xiantai Street, Erdao District, Changchun 130033, China. FAU - Zhang, Qiao AU - Zhang Q AD - Department of Orthopedics, China-Japan Union Hospital of Jilin University, No. 126 of Xiantai Street, Erdao District, Changchun 130033, China. FAU - Yu, Tao AU - Yu T AD - Department of Orthopedics, Second Hospital of Jilin University, Changchun 130000, China. FAU - Sun, Shudong AU - Sun S AD - Department of Orthopedics, Second Hospital of Jilin University, Changchun 130000, China. FAU - Wang, Wenjun AU - Wang W AD - Department of Orthopedics, China-Japan Union Hospital of Jilin University, No. 126 of Xiantai Street, Erdao District, Changchun 130033, China. FAU - Liu, Guangyao AU - Liu G AD - Department of Orthopedics, China-Japan Union Hospital of Jilin University, No. 126 of Xiantai Street, Erdao District, Changchun 130033, China. LA - eng PT - Journal Article DEP - 20160128 PL - Netherlands TA - J Bone Oncol JT - Journal of bone oncology JID - 101610292 PMC - PMC4782021 OTO - NOTNLM OT - AMPK signaling OT - Doxorubicin OT - Hypoxia OT - Osteosarcoma cells OT - Resistance EDAT- 2016/03/22 06:00 MHDA- 2016/03/22 06:01 PMCR- 2016/01/28 CRDT- 2016/03/22 06:00 PHST- 2015/12/06 00:00 [received] PHST- 2016/01/07 00:00 [revised] PHST- 2016/01/12 00:00 [accepted] PHST- 2016/03/22 06:00 [entrez] PHST- 2016/03/22 06:00 [pubmed] PHST- 2016/03/22 06:01 [medline] PHST- 2016/01/28 00:00 [pmc-release] AID - S2212-1374(15)30081-6 [pii] AID - 10.1016/j.jbo.2016.01.002 [doi] PST - epublish SO - J Bone Oncol. 2016 Jan 28;5(1):22-9. doi: 10.1016/j.jbo.2016.01.002. eCollection 2016 Mar.