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Review
. 2022 Dec 15;12(12):1882.
doi: 10.3390/biom12121882.

Mechanism and Role of Endoplasmic Reticulum Stress in Osteosarcoma

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Review

Mechanism and Role of Endoplasmic Reticulum Stress in Osteosarcoma

Peijun Zhu et al. Biomolecules. .

Abstract

Osteosarcoma is the most common malignant bone tumor, often occurring in children and adolescents. The etiology of most patients is unclear, and the current conventional treatment methods are chemotherapy, radiotherapy, and surgical resection. However, the sensitivity of osteosarcoma to radiotherapy and chemotherapy is low, and the prognosis is poor. The development of new and useful treatment strategies for improving patient survival is an urgent need. It has been found that endoplasmic reticulum (ER) stress (ERS) affects tumor angiogenesis, invasion, etc. By summarizing the literature related to osteosarcoma and ERS, we found that the unfolded protein response (UPR) pathway activated by ERS has a regulatory role in osteosarcoma proliferation, apoptosis, and chemoresistance. In osteosarcoma, the UPR pathway plays an important role by crosstalk with autophagy, oxidative stress, and other pathways. Overall, this article focuses on the relationship between ERS and osteosarcoma and reviews the potential of drugs or gene targets associated with ERS for the treatment of osteosarcoma.

Keywords: autophagy; endoplasmic reticulum stress; osteosarcoma; oxidative stress; therapy; unfolded protein response.

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Conflict of interest statement

The authors have no competing interests to declare that are relevant to the content of this article.

Figures

Figure 1
Figure 1
The three branches of the endoplasmic reticulum stress response (ERS) and the unfolded protein response (UPR). When unfolded or misfolded proteins accumulate, the UPR is triggered in the cell to restore endoplasmic reticulum homeostasis. The UPR is transduced by three sensors: IRE1, PERK, and ATF6. Under ERS, Bip is separated from each of the three sensors, which allows them to be activated and subsequently activates downstream transcription factors that promote the expression of UPR target genes (ERAD components, CHOP, and ER chaperones). IRE1 is also involved in the regulated IRE1-dependent decay (RIDD) process to reduce the quantity of proteins entering the ER and alleviate ERS. This figure has been created with https://app.biorender.com (accessed on 20 July 2022).
Figure 2
Figure 2
Crosstalk of ERS with autophagy and oxidative stress. The intracellular induction of the Sestrin2/PERK/p-eIF2α/CHOP/mTOR/autophagy axis protects osteosarcoma cells during chemotherapy, leading to the chemoresistance of cells. The intracellular induction of apoptosis via the PERK/p-eIF2α/CHOP/mTOR/autophagy axis and IRE1/TRAF2/ASK1/JNK/autophagy pathway in osteosarcoma cells during high LET radiation treatment induces cellular sensitivity to strong LET radiation. When CYT997 and bortezomib in combination with adriamycin were used to treat osteosarcoma, intracellularly generated oxidative stress induced apoptosis through PERK/eIF2α/CHOP axis regulation. When combined photodynamic therapy was administered, intracellularly triggered oxidative stress in osteosarcoma cells induced apoptosis through JNK/p53/p21 pathway regulation. This figure has been created using https://app.biorender.com (accessed on 20 July 2022).

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