Sestrin2-Mediated Autophagy Contributes to Drug Resistance via Endoplasmic Reticulum Stress in Human Osteosarcoma.

Zhen Tang,Feilong Wei,Hui Dong,Xiaokang Li,Xin Xiao,Tian Li,Xinghui Wei,Zheng Guo,Yichao Liu,Lei Shi,Hao Wu,Wei Wang

doi:10.3389/fcell.2021.722960

Abstract

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.

Highlights

Neoplasms remain the primary killer worldwide (Burns et al, 2020; Pantziarka et al, 2021)
We found that SESN2 expression was upregulated in osteosarcoma cells during chemotherapy; we further investigated the effects of SESN2 on the proliferation, apoptosis, drug resistance of osteosarcoma cells
To analyse the expression of SESN2 in osteosarcoma cells after chemotherapy, we detected the expression of SESN2 in HOS, MG63 and 143B cells treated with Cis (20 μmol/L), Dox (0.2 μg/mL) or Mtx (50 μmol/L)

Summary

Introduction

Neoplasms remain the primary killer worldwide (Burns et al, 2020; Pantziarka et al, 2021). To develop more effective and comprehensive treatments for clinical application, it is necessary to identify the underlying mechanisms relating to the proliferation, drug resistance and recurrence of osteosarcoma (Gu et al, 2018; Liu et al, 2021). Some studies have suggested that autophagy can induce programmed death of tumour cells and inhibit tumorigenesis and metastasis (Mrakovcic and Frohlich, 2019). Autophagy is believed to inhibit the exposure of cancer cells to accumulated damage and reduce apoptosis, and enhance the viability of cancer cells, thereby promoting tumour proliferation, drug resistance and metastasis (Wang et al, 2019). The relationship between autophagy and apoptosis, and the underlying mechanism of autophagy in drug resistance of osteosarcoma remains unclear (Hattori et al, 2021)

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