Data_Sheet_12_Sestrin2-Mediated Autophagy Contributes to Drug Resistance via Endoplasmic Reticulum Stress in Human Osteosarcoma.ZIP

One contributor to the high mortality of osteosarcoma is its reduced sensitivity to chemotherapy, but the mechanism involved is unclear. Improving the sensitivity of osteosarcoma to chemotherapy is urgently needed to improve patient survival. We found that chemotherapy triggered apoptosis of human osteosarcoma cells in vitro and in vivo; this was accompanied by increased Sestrin2 expression. Importantly, autophagy was also enhanced with increased Sestrin2 expression. Based on this observation, we explored the potential role of Sestrin2 in autophagy of osteosarcoma. We found that Sestrin2 inhibited osteosarcoma cell apoptosis by promoting autophagy via inhibition of endoplasmic reticulum stress, and this process is closely related to the PERK-eIF2α-CHOP pathway. In addition, our study showed that low Sestrin2 expression can effectively reduce autophagy of human osteosarcoma cells after chemotherapy, increase p-mTOR expression, decrease Bcl-2 expression, promote osteosarcoma cell apoptosis, and slow down tumour progression in NU/NU mice. Sestrin2 activates autophagy by inhibiting mTOR via the PERK-eIF2α-CHOP pathway and inhibits apoptosis via Bcl-2. Therefore, our results explain one underlying mechanism of increasing the sensitivity of osteosarcoma to chemotherapy and suggest that Sestrin2 is a promising gene target.

骨肉瘤的高死亡率之一源于其对化疗的敏感性降低，但其涉及的机制尚不明确。为提升骨肉瘤对化疗的敏感性，以改善患者生存率，实为当务之急。本研究发现，化疗可诱导体外及体内的人骨肉瘤细胞发生凋亡，并伴随Sestrin2表达水平的上升。值得注意的是，Sestrin2表达水平的增加亦促进了自噬作用。基于此观察结果，我们探讨了Sestrin2在骨肉瘤自噬过程中的潜在作用。研究发现，Sestrin2通过抑制内质网应激，促进自噬作用，从而抑制骨肉瘤细胞的凋亡，此过程与PERK-eIF2α-CHOP通路密切相关。此外，我们的研究还表明，低水平的Sestrin2表达可有效降低化疗后的人骨肉瘤细胞自噬，增加p-mTOR表达，降低Bcl-2表达，促进骨肉瘤细胞的凋亡，并减缓NU/NU小鼠的肿瘤进展。Sestrin2通过PERK-eIF2α-CHOP通路抑制mTOR激活自噬，通过Bcl-2抑制凋亡。因此，我们的研究结果阐释了提高骨肉瘤对化疗敏感性的潜在机制，并提示Sestrin2可作为基因治疗的潜在靶点。