Data_Sheet_5_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.

骨肉瘤高死亡率的重要成因之一是肿瘤对化疗的敏感性降低，但其相关分子机制尚未阐明。为改善患者生存预后，亟需探索提高骨肉瘤化疗敏感性的有效策略。本研究发现，化疗可在体内外诱导人骨肉瘤细胞发生凋亡，同时伴随Sestrin2表达水平上调；值得注意的是，细胞自噬（autophagy）水平也随Sestrin2表达升高而显著增强。基于上述观察结果，本研究探讨了Sestrin2在骨肉瘤细胞自噬中的潜在作用。结果显示，Sestrin2可通过抑制内质网应激（endoplasmic reticulum stress）增强细胞自噬，进而抑制骨肉瘤细胞凋亡，且该过程与PERK-eIF2α-CHOP信号通路密切相关。此外，本研究证实，低表达Sestrin2可有效降低化疗后人骨肉瘤细胞的自噬水平，上调磷酸化mTOR（p-mTOR）的表达，下调B细胞淋巴瘤因子2（Bcl-2）的表达，促进骨肉瘤细胞凋亡，并可减缓NU/NU裸鼠的肿瘤进展速度。Sestrin2可通过PERK-eIF2α-CHOP信号通路抑制mTOR活性以激活细胞自噬，并通过调控Bcl-2的表达抑制细胞凋亡。综上，本研究结果阐明了提高骨肉瘤化疗敏感性的潜在分子机制之一，并提示Sestrin2是一个极具应用前景的基因治疗靶点。