Patients with metastatic or relapsed/refractory osteosarcoma (OS) have a 5-year survival rate of <30%. This has remained unchanged over several decades. One of the factors contributing to lack of improvement in survival is the development of chemoresistance. Hence, elucidating and targeting the mechanisms that promote survival against chemotherapy and lead to chemoresistance is pivotal to improving outcomes for these patients. We identified that endoplasmic reticulum (ER) stress-activated transcription factor, ATF6α, is essential for the survival of OS cells against chemotherapy induced cell death. ATF6α cleavage and activity were enhanced in OS cells compared to normal osteoblasts and knockdown of ATF6α expression enhanced sensitivity of OS cells against chemotherapy induced cell death. This was in part due to increased Bax activation. Pharmacologic inhibition or knock-down of downstream targets of ATF6α, protein disulfide isomerases (PDI) and ERO1β, a thiol oxidase that is involved in the re-oxidation of PDIs also independently induced pronounced killing of OS cells following chemotherapy. Analysis of primary tumors from OS patients reveals that patients with high levels of nuclear ATF6α: (1) also had increased expression of its downstream targets the chaperone BiP and enzyme PDI, (2) had a significant likelihood of developing metastasis at diagnosis, (3) had significantly poorer overall and progression free survival, and (4) had poorer response to chemotherapy. These findings suggest that targeting survival signaling by the ATF6α pathway in OS cells may favor eradication of refractory OS tumor cells and ATF6α could be a useful predictor for chemo-responsiveness and prognosis.

转移性或复发性/难治性骨肉瘤（OS）患者的5年生存率<30％。几十年来一直保持不变。导致存活率缺乏改善的因素之一是化学抗性的发展。因此，阐明和靶向能提高针对化学疗法的存活率并导致化学耐药性的机制，对于改善这些患者的预后至关重要。我们确定内质网（ER）应力激活的转录因子ATF6α，对于OS细胞抵抗化疗诱导的细胞死亡的生存至关重要。与正常成骨细胞相比，OS细胞中的ATF6α裂解和活性增强，而敲除ATF6α表达则增强了OS细胞对化疗诱导的细胞死亡的敏感性。这部分是由于增加了Bax激活。ATF6α，蛋白二硫键异构酶（PDI）和ERO1β（一种参与PDI的再氧化的硫醇氧化酶）下游靶标的药理抑制或抑制作用也可独立诱导化疗后OS细胞的明显杀伤。对OS患者的原发肿瘤的分析表明，核ATF6α含量高的患者：（1）其下游靶标的分子伴侣BiP和PDI酶的表达也有所增加;（2）诊断时很可能发生转移，（3） ）的总体生存和无进展生存期显着较差，并且（4）对化学疗法的响应较差。这些发现表明，通过ATF6α途径在OS细胞中靶向生存信号可能有助于根除难治性OS肿瘤细胞，并且ATF6α可能是化学反应性和预后的有用预测因子。