Hypoxia promotes drug resistance in osteosarcoma cells via activating AMP-activated protein kinase (AMPK) signaling

Abstract

PurposeDrug 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 designWe 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)α and HIF-1β, the activation and regulatory role of AMPK in the osteosarcoma U2-os cells which were treated with doxorubicin under hypoxia.ResultsIt 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-1α, 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.ConclusionThe 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.

Mxd1 mediates hypoxia‐induced cisplatin resistance in osteosarcoma cells by repression of the PTEN tumor suppressor gene

“…The hypoxic tumor micro‐environment is an important factor for drug resistance development . Hypoxia‐induced chemoresistance to commonly used chemotherapeutic drugs, such as cisplatin (CDDP), doxorubicin, 5‐flouoruracil, and docetaxel has been previously reported in a number of tumor cell types . Although different approaches are continuously being developed in an effort to circumvent hypoxia‐induced chemoresistance, the outcomes have been limited.…”

“…Adaptation of tumor cells to hypoxic conditions also contributes to their chemoresistance . Hypoxia has been previously reported to confer resistance to commonly used chemotherapy drugs, such as cisplatin (CDDP) . Hypoxia‐mediated chemoresistance is an important obstacle to effective cancer treatment.…”

“…Thus, overcoming hypoxia‐induced chemoresistance would change an impediment into an advantage for developing anticancer therapy. Recently, the mechanisms underlying hypoxia‐induced chemoresistance have gained increasing attention . Although many mechanisms have been suggested to be responsible for the hypoxia‐induced chemoresistance, the real mechanisms are complicated and vary depending on the cell types.…”

“…5,8 Hypoxia has been previously reported to confer resistance to commonly used chemotherapy drugs, such as cisplatin (CDDP). 9,10 Hypoxia-mediated chemoresistance is an important obstacle to effective cancer treatment. Thus, overcoming hypoxiainduced chemoresistance would change an impediment into an advantage for developing anticancer therapy.…”

Myeloid‐derived suppressor cells as effectors of immune suppression in cancer

“…Hypoxia is a common feature of solid tumors as they outgrow their blood supply, and has implicated in mediating resistance to chemotherapy, the promotion of metastases, as well as resulting in an immune privilaged niche . Hypoxia has been shown to promote the expansion of immune‐suppressive MDSCs, as well as mediating the differentiation of MDSCs into immune‐suppressive tumor associated macrophages (TAMs), upon arrival in the hypoxic tumor bed …”