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A Syngeneic Orthotopic Osteosarcoma Sprague Dawley Rat Model with Amputation to Control Metastasis Rate
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CDK7/GRP78 signaling axis contributes to tumor growth and metastasis in osteosarcoma

Tao Zhang1, Jingjie Li2, Mengkai Yang3

  • 1Department of Orthopedics, Shanghai Bone Tumor Institution, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, P. R. China. zhangtaoabc@2008.sina.com.

Oncogene
|August 30, 2022
PubMed

Insights

This study reveals a new signaling pathway involving Cyclin-Dependent Kinase 7 (CDK7) and Glucose-Regulated Protein 78 (GRP78) in osteosarcoma. Targeting this axis with CDK7 inhibitors shows promise for treating this bone cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • Osteosarcoma is the most common primary bone malignancy, originating from mesenchymal cells.
  • Current therapeutic strategies for osteosarcoma have limited success, necessitating the identification of novel therapeutic targets.
  • Understanding the underlying molecular mechanisms is crucial for developing new treatment options.

Purpose of the Study:

  • To investigate the novel mechanism by which Cyclin-Dependent Kinase 7 (CDK7) regulates osteosarcoma.
  • To explore the molecular association between CDK7 and Glucose-Regulated Protein 78 (GRP78) in osteosarcoma.
  • To provide theoretical support for the use of CDK7 inhibitors in osteosarcoma treatment.

Main Methods:

  • Investigated the interaction between CDK7 and GRP78 in osteosarcoma cells.
  • Examined the role of the E3 ubiquitin ligase TRIM21 in GRP78 degradation.
  • Utilized a specific CDK7 inhibitor, THZ1, to assess its effects on osteosarcoma growth and metastasis.

Main Results:

  • CDK7 phosphorylates GRP78 at T69, inhibiting TRIM21-mediated ubiquitination and degradation, thus stabilizing GRP78.
  • The CDK7 inhibitor THZ1 effectively reduced osteosarcoma growth and metastasis.
  • Combined inhibition of CDK7 and GRP78 demonstrated additive effects in suppressing osteosarcoma progression.

Conclusions:

  • A novel CDK7/GRP78 signaling axis was identified in osteosarcoma.
  • This axis provides a molecular basis for targeting CDK7 and GRP78 simultaneously for osteosarcoma treatment.
  • Simultaneous suppression of CDK7 and GRP78 activity represents a potential therapeutic strategy for osteosarcoma.

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