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A Syngeneic Orthotopic Osteosarcoma Sprague Dawley Rat Model with Amputation to Control Metastasis Rate
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PERK-mediated Autophagy in Osteosarcoma Cells Resists ER Stress-induced Cell Apoptosis

Guang-rong Ji1, Nai-chun Yu1, Xiang Xue1

  • 1Department of Orthopaedics, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, 150001, China.

International Journal of Biological Sciences
|June 17, 2015
PubMed

Insights

Autophagy promotes osteosarcoma chemoresistance by activating PERK and inhibiting mTORC1, leading to apoptosis resistance. Suppressing PERK-mediated autophagy enhances cancer cell death, offering a new therapeutic target.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cellular Stress Response

Background:

  • Osteosarcoma, a common bone cancer in children and adolescents, frequently develops chemoresistance.
  • The molecular mechanisms underlying osteosarcoma chemoresistance, particularly resistance to apoptosis, are not fully understood.
  • Autophagy, a cellular degradation process, is increasingly recognized for its role in cancer survival and drug resistance.

Purpose of the Study:

  • To investigate the role of autophagy in mediating chemoresistance to apoptosis in osteosarcoma cells.
  • To elucidate the specific molecular pathways involved, focusing on the PERK (double-elated kinase R) pathway and endoplasmic reticulum (ER) stress.
  • To determine if targeting PERK-mediated autophagy could represent a novel therapeutic strategy for osteosarcoma.

Main Methods:

  • Immunohistochemistry and Western blotting were used to assess PERK activation and autophagy markers in osteosarcoma cells.
  • The mTORC1 (mammalian target of rapamycin complex 1) pathway activity was evaluated in relation to PERK signaling.
  • RNA interference (RNAi) was employed to specifically knock down PERK expression and observe its effects on autophagy and apoptosis.

Main Results:

  • PERK activation was found to induce autophagy in osteosarcoma cells by inhibiting the mTORC1 pathway.
  • This PERK-mediated autophagy significantly contributed to resistance against apoptosis, promoting cancer cell survival.
  • Knockdown of PERK using RNAi suppressed autophagy, leading to increased apoptosis in osteosarcoma cells.

Conclusions:

  • PERK-mediated autophagy plays a critical role in promoting osteosarcoma cell survival by conferring resistance to apoptosis.
  • The findings highlight a novel mechanism of chemoresistance linked to ER stress and autophagy in osteosarcoma.
  • Targeting the PERK-autophagy axis presents a promising new therapeutic avenue for overcoming chemoresistance in osteosarcoma treatment.
Keywords:
ER stressPERKautophagymTORC1osteosarcoma

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